Efficacy of administration sequence: Sacituzumab Govitecan and Trastuzumab Deruxtecan in HER2-low metastatic breast cancer.

BACKGROUND: Current guidelines recommend that patients with HER2-low metastatic breast cancer (MBC) receive sequentially two antibody-drug conjugates (ADCs): Sacituzumab Govitecan (SG) and Trastuzumab Deruxtecan (T-DXd), despite a similar payload. However, the effectiveness of one after another is unknown. METHODS: ADC-Low is a multicentre, retrospective study evaluating the efficacy of SG and T-DXd, one after another, with or without intermediary lines of chemotherapy, in patients with HER2-low MBC. RESULTS: One hundred and seventy-nine patients were included: the majority with HR-negative tumours received SG first (ADC1) (n = 100/108) while most with HR-positive tumours received T-DXd first (n = 56/71). Median progression-free survival 2 was short: 2.7 months (95% CI: 2.4-3.3) in the whole population, respectively, 3.1 (95% CI: 2.6-3.6) and 2.2 months (95% CI: 1.9-2.7) for patients receiving T-DXd or SG second (ADC2). Intermediary lines of chemotherapy between ADC1 and ADC2 had no impact. Primary resistance to ADC2 occurred in 54.4% of patients. Certain patients showed initial response to ADC2. CONCLUSIONS: Clinical benefit of sequentially administered SG and T-DXd is limited for most patients. Nevertheless, a subset of patients might benefit-on the short term-from a second ADC. Additional studies are needed to identify patients who could benefit from two ADCs with similar payloads.

Efficacy of front-line treatment for hormone receptor-positive HER2-negative metastatic breast cancer with germline BRCA1/2 mutation.

BACKGROUND: Efficacy of endocrine therapy in HR+/HER2- metastatic breast cancer could differ depending on the presence of BRCA1/2 germline mutation. METHODS: The ESME metastatic breast cancer platform (NCT03275311) is a French real world database. Multivariable models including a time-varying approach and landmark analyses assessed the association between time-dependent gBRCA status (categorised as gBRCAm, gBRCAwt (wild type), and untested), overall survival (OS), and first-line progression-free survival (PFS1). RESULTS: A total of 170 patients were gBRCAm carriers, 676 gBRCAwt, and 12,930 were untested at baseline. In the multivariable analysis, gBRCAm carriers overall had a lower OS compared to gBRCAwt (adjusted HR [95% CI] 1.26 [1.03-1.55]). gBRCAm patients treated with front-line endocrine therapy had lower adjusted OS (adjusted HR [95% CI] = 1.54 [1.03-2.32]) and PFS1 (adjusted HR [95% CI] 1.58 [1.17-2.12]) compared to gBRCAwt patients. However, for patients who received frontline chemotherapy, neither OS nor PFS1 differed between gBRCAm carriers and the other groups (HR versus gBRCAwt for OS: 1.12 [0.88-1.41], p = 0.350; PFS1: 1.09 [0.90-1.31], p = 0.379). CONCLUSION: In this large cohort of HR+/HER2- MBC patients treated in a pre-CDK4/6 inhibitors era, gBRCAm status was associated with a lower OS and lower PFS following first-line endocrine therapy, but not following first-line chemotherapy.

Enrollment of older metastatic breast cancer patients in first-line clinical trials: 9-year experience of the large-scale real-life multicenter French ESME cohort.

PURPOSE: Older cancer patients are underrepresented in clinical trials. We aimed to evaluate the enrollment of older women aged 70 years old (yo) or over with metastatic breast cancer (MBC) in clinical trials. METHODS: We used the national Epidemio-Strategy and Medical Economics MBC Data Platform, a French multi-center real-life database. We selected MBC women over 70yo, without central nervous system metastases, with at least one line of systemic treatment, between January 1st, 2008 and December 31st, 2016, and had no other cancer in the 5 years before MBC. The primary objective was to evaluate the proportion of patients enrolled in clinical trials according to their age. Secondary objective was to identify variables associated with enrollment in older ones. RESULTS: 5552 women were aged ≥ 70 (median 74yo; IQR 72-77). 14,611 were less than 70. Of the older ones, 239 (4%) were enrolled in a clinical trial during first line of treatment, compared with 1529 (10.5%) for younger ones. Multivariable analysis of variables predicting for enrollment during first line of treatment in older patients were younger age (OR 0.50 [95%CI 0.33-0.76] for the 80-85yo class; OR 0.17 [95%CI 0.06-0.39] for the 85yo and more class), good ECOG Performance Status (PS 0-1) (OR 0.15 [95%CI 0.08-0.27] for the PS 2-4 class), HER2 + disease (OR 1.78 [95%CI 1.27-2.48]), type of treatment (chemotherapy/targeted therapy/immunotherapy OR 5.01 [95%CI 3.13-8.18]), and period (OR 1.65 [95%CI 1.22-2.26] for 2012-2016, compared to 2008-2011). CONCLUSION: In this large database, few older MBC patients were enrolled in a trial compared with younger ones.

Magnesium(II)-ATP Complexes in 1-Ethyl-3-Methylimidazolium Acetate Solutions Characterized by 31 Mg ß-Radiation-Detected NMR Spectroscopy.

The complexation of MgII with adenosine 5'-triphosphate (ATP) is omnipresent in biochemical energy conversion, but is difficult to interrogate directly. Here we use the spin- 1/2 ß-emitter 31 Mg to study MgII -ATP complexation in 1-ethyl-3-methylimidazolium acetate (EMIM-Ac) solutions using ß-radiation-detected nuclear magnetic resonance (ß-NMR). We demonstrate that (nuclear) spin-polarized 31 Mg, following ion-implantation from an accelerator beamline into EMIM-Ac, binds to ATP within its radioactive lifetime before depolarizing. The evolution of the spectra with solute concentration indicates that the implanted 31 Mg initially bind to the solvent acetate anions, whereafter they undergo dynamic exchange and form either a mono- (31 Mg-ATP) or di-nuclear (31 MgMg-ATP) complex. The chemical shift of 31 Mg-ATP is observed up-field of 31 MgMg-ATP, in accord with quantum chemical calculations. These observations constitute a crucial advance towards using ß-NMR to probe chemistry and biochemistry in solution.

VA Home Based Primary Care Teams: Partnering with and Acting as Caregivers for Veterans.

The U.S. Department of Veterans Affairs' Home-Based Primary Care (HBPC) Interdisciplinary Team (IDT) provides in-home, primary care for medically complex Veterans. This study explores how HBPC and Veterans' caregivers partner to provide care. Interviews, focus groups, and field observations were conducted during eight HBPC site visits. Qualitative thematic analysis was performed. Caregivers/IDT member partnerships are important to care. Effective partnerships include: ease of communication; caregiver-centered support; and when no caregiver is present, IDTs providing more monitoring/services to Veterans and connection to community services. As this model expands, understanding dynamics between IDT members and caregivers will optimize the success of HBPC programs.

Open-label randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer.

Background: There is no standard treatment after progression on second-line chemotherapy for metastatic breast cancer (MBC). We compared vinflunine with physician's choice of alkylating agent (AA) for patients with heavily pretreated MBC. Patients and methods: In this open-label phase III trial, patients with MBC were included if they had received at least two prior chemotherapy regimens for MBC and had received anthracycline, taxane, antimetabolite and vinca alkaloid therapy. Patients were no longer candidates for these chemotherapies because of resistance and/or intolerance. Patients were randomised to either vinflunine 280 mg/m2 intravenously every 3 weeks (q3w) or AA monotherapy q3w. Stratification factors were performance status, number of prior chemotherapy lines for MBC, disease measurability and study site. The primary end point was overall survival (OS). Results: A total of 594 patients were randomised (298 to vinflunine, 296 to AA). There was no difference between treatment arms in OS (hazard ratio 1.04, P = 0.67; median 9.1 months for vinflunine versus 9.3 months for AA), progression-free survival (hazard ratio 0.94, P = 0.49; median 2.5 versus 1.9 months, respectively) or overall response rate (6% versus 4%, respectively). However, the disease control rate was significantly higher with vinflunine than AA (44% versus 35%, respectively; P = 0.04). The most common adverse events (any grade) were haematological and gastrointestinal disorders and asthenia in both arms. The most common grade 3/4 adverse events were neutropenia (19% versus 11% with vinflunine versus AA, respectively) and asthenia (10% versus 4%). Conclusions: Vinflunine 280 mg/m2 q3w did not improve OS compared with the physician's choice of AA as third- or later-line therapy for MBC. Vinflunine demonstrated an acceptable safety profile, suggesting that vinflunine 320 mg/m2 merits evaluation. ClinicalTrials.gov: NCT01091168.

Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer.

Background: Palbociclib is a CDK4/6 inhibitor with demonstrated efficacy and safety in combination with endocrine therapy in advanced luminal breast cancer (LBC). We evaluated the respective efficacy and safety of chemotherapy and letrozole-palbociclib (LETPAL) combination as neoadjuvant treatment in patients with high-risk LBC. Patients and methods: NeoPAL (UCBG10/4, NCT02400567) is a randomised, parallel, non-comparative phase II study. Patients with ER-positive, HER2-negative, Prosigna®-defined luminal B, or luminal A and node-positive, stage II-III breast cancer, not candidate for breast-conserving surgery, were randomly assigned to either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks/4) during 19 weeks, or to FEC100 (5FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2)×3 21-day courses followed by docetaxel 100 mg/m2×3 21-day courses. Primary end point was residual cancer burden (RCB 0-I rate). Secondary end points included clinical response, proliferation-based markers, and safety. Results: Overall, 106 patients were randomised [median Prosigna® ROR Score 71 (22-93)]. RCB 0-I was observed in four and eight patients in LETPAL [7.7% (95% CI 0.4-14.9)] and chemotherapy [15.7% (95% CI 5.7-25.7)] arms, respectively. Pathological complete response rates were 3.8% and 5.9%. Clinical response (75%) and breast-conserving surgery rates (69%) were similar in both arms. Preoperative Endocrine Prognostic Index 0 scores (breast cancer-specific survival) were observed in 17.6% and 8.0% of patients in LETPAL and chemotherapy arms, respectively. Safety profile was as expected, with 2 versus 17 serious adverse events (including 11 grade 4 serious AEs in the chemotherapy arm). Conclusion: LETPAL combination was associated with poor pathological response but encouraging clinical and biomarker responses in Prosigna®-defined high-risk LBC. Contemporary chemotherapy regimen was associated with poor pathological and biomarker responses, with a much less favourable safety profile. LETPAL combination might represent an alternative to chemotherapy in early high-risk LBC. Clinical Trial Number: NCT02400567.

Direct measurements of the temperature, depth and processing dependence of phenyl ring dynamics in polystyrene thin films by ß-detected NMR.

There is indirect evidence that the dynamics of a polymer near a free surface are enhanced compared with the bulk but there are few studies of how dynamics varies with depth. ß-Detected nuclear spin relaxation of implanted 8Li+ has been used to directly probe the temperature and depth dependence of the γ-relaxation mode, which is due to phenyl rings undergoing restricted rotation, in thin films of atactic deuterated polystyrene (PS-d8) and determine how the depth dependence of dynamics is affected by sample processing, such as annealing, floating on water and the inclusion of a surfactant, and by the presence of a buried interface. The activation energy for the γ-relaxation process is lower near the free surface. Annealing the PS-d8 films and then immersing in water to mimic the floating procedure used to transfer films had negligible effects on the thickness of the region near the free surface with enhanced mobility. Measurements on a bilayer film indicate enhanced phenyl ring dynamics near the buried interface compared with a single film at the same depth. PS-d8 films annealed with the surfactant sodium dodecyl sulfate (SDS) deposited on the surface show enhanced dynamics in the bulk compared with a pure PS-d8 film and a PS-d8 film where the SDS was washed away. There is less contrast between the surface and bulk in the SDS-treated sample, which could account for the elimination of the Tg confinement effect observed in films containing SDS [Chen and Torkelson, Polymer, 2016, 87, 226].

Circulating tumour cells and pathological complete response: independent prognostic factors in inflammatory breast cancer in a pooled analysis of two multicentre phase II trials (BEVERLY-1 and -2) of neoadjuvant chemotherapy combined with bevacizumab.

Background: We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab. Patients and methods: Nonmetastatic T4d patients were enrolled in two phase II multicentre trials, evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy of four cycles of FEC followed by four cycles of docetaxel in HER2-negative tumour (BEVERLY-1) or docetaxel and trastuzumab in HER2-positive tumour (BEVERLY-2). CTC and CEC were detected in 7.5 and 4 ml of blood, respectively, with the CellSearch System. Results: From October 2008 to September 2010, 152 patients were included and 137 were evaluable for CTC and CEC. At baseline, 55 patients had detectable CTC (39%). After four cycles of chemotherapy, a dramatic drop in CTC to a rate of 9% was observed (P < 0.01). Pathological complete response (pCR) rate was 40%. No correlation was found between CTC or CEC levels and pCR rate. Median follow-up was 43 months. CTC detection (≥1 CTC/7.5 ml) at baseline was associated with shorter 3-year disease-free survival (39% versus 70% for patients without CTC, P < 0.01, HR 2.80) and shorter 3-year overall survival (OS) (P < 0.01). In multivariate analysis, independent prognostic parameters for shorter survival were absence of hormonal receptors, no pCR and CTC detection at baseline. CEC level at baseline or variations during treatment had no prognostic value. Conclusion: In this pooled analysis of two prospective trials in nonmetastatic IBC, detection rate of CTC was 39% with a strong and independent prognostic value for survival. Combination of pCR after neoadjuvant treatment with no CTC detection at baseline isolated a subgroup of IBC with excellent OS (94% 3-year OS), suggesting that CTC count could be part of IBC stratification in prospective trials.

ß-NMR measurements of molecular-scale lithium-ion dynamics in poly(ethylene oxide)-lithium-salt thin films.

ß-detected NMR (ß-NMR) has been used to study the molecular-scale dynamics of lithium ions in thin films of poly(ethylene oxide) (PEO) containing either lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) or lithium trifluoroacetate (LiTFA) salts at monomer-to-salt ratios (EO/Li) of 8.3. The results are compared with previous ß-NMR measurements on pure PEO and PEO with lithium triflate (LiOTf) at the same loading [McKenzie et al., J. Am. Chem. Soc. 136, 7833 (2014)]. Activated hopping of 8Li+ was observed in all of the films above ∼250 K, with the hopping parameters strongly correlated with the ionicity of the lithium salt rather than the polymer glass transition temperature. The pre-exponential factor increases exponentially with ionicity, while the activation energy for hopping increases approximately linearly, going from 6.3±0.2 kJ mol-1 in PEO:LiTFA to 17.8±0.2 kJ mol-1 in PEO:LiTFSI. The more rapid increase in the pre-exponential factor outweighs the effect of the larger activation energy and results in 8Li+ hopping being fastest in PEO followed by PEO:LiTFSI, PEO:LiOTf, and PEO:LiTFA.

Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer.

BACKGROUND: The randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone [hazard ratio (HR) = 0.75, 95% confidence interval (CI) 0.61-0.93]. We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy, but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety. RESULTS: Of the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR = 0.79, 95% CI 0.59-1.06), combined second- and third-line PFS (HR = 0.85, 95% CI 0.68-1.05) or OS (HR = 0.96, 95% CI 0.76-1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected. CONCLUSIONS: In this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS, but no improvement in longer term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life. CLINICALTRIALSGOV: NCT01250379.

Paclitaxel plus bevacizumab or paclitaxel as first-line treatment for HER2-negative metastatic breast cancer in a multicenter national observational study.

BACKGROUND: Bevacizumab combined with paclitaxel as first-line chemotherapy for patients with HER2-negative metastatic breast cancer (MBC) has led to mixed results in randomized trials, with an improvement in progression-free survival (PFS) but no statistically significant overall survival (OS) benefit. Real-life data could help in assessing the value of this combination. PATIENTS AND METHODS: This study aimed to describe the outcome following first-line paclitaxel with or without bevacizumab in the French Epidemiological Strategy and Medical Economics (ESME) database of MBC patients, established in 2014 by Unicancer. The primary and secondary end points were OS and PFS, respectively. RESULTS: From 2008 to 2013, 14 014 MBC patient files were identified, including 10 605 patients with a HER2-negative status. Of these, 3426 received paclitaxel and bevacizumab (2127) or paclitaxel (1299) as first-line chemotherapy. OS adjusted for major prognostic factors was significantly longer in the paclitaxel and bevacizumab group compared with paclitaxel [hazard ratio (HR) 0.672, 95% confidence interval (CI) 0.601-0.752; median survival time 27.7 versus 19.8 months]. Results were consistent in all supportive analyses (using a propensity score for adjustment and as a matching factor for nested case-control analyses) and sensitivity analyses. Similar results were observed for the adjusted PFS, favoring the combination (HR 0.739, 95% CI 0.672-0.813; 8.1 versus 6.4 months). CONCLUSIONS: In this large-scale, real-life setting, patients with HER2-negative MBC who received paclitaxel plus bevacizumab as first-line chemotherapy had a significantly better OS and PFS than those receiving paclitaxel. Despite robust methodology, real-life data are exposed to important potential biases, and therefore, results need to be treated with caution. Our data cannot therefore support extension of current use of bevacizumab in MBC.

ß-NMR Investigation of the Depth-Dependent Magnetic Properties of an Antiferromagnetic Surface.

By measuring the prototypical antiferromagnet α-Fe_{2}O_{3}, we show that it is possible to determine the static spin orientation and dynamic spin correlations within nanometers from an antiferromagnetic surface using the nuclear spin polarization of implanted ^{8}Li^{+} ions detected with ß-NMR. Remarkably, the first-order Morin spin reorientation in single crystal α-Fe_{2}O_{3} occurs at the same temperature at all depths between 1 and 100 nm from the (110) surface; however, the implanted nuclear spin experiences an increased 1/T_{1} relaxation rate at shallow depths revealing soft-surface magnons. The surface-localized dynamics decay towards the bulk with a characteristic length of ε=11±1 nm, closely matching the finite-size thresholds of hematite nanostructures.

[Social representations of illness: Comparison of "expert" knowledge and "naïve" knowledge]. / Représentations sociales de la maladie : comparaison entre savoirs « experts ¼ et savoirs « profanes ¼.

INTRODUCTION: The link between social practices and representations is now well known. But while many studies have focused on the social representation of mental illness, in various populations, few studies have focused on the notion of disease/illness by comparing professionals and non-professionals health workers representations. Indeed, the disease is both a reality described, explained and treated by medicine; for those who are affected by a disease, it is an individual experience with psychological, social and cultural impacts. The social representation is determined by the structure of the social groups in which it develops; therefore, it is a form of knowledge socially shaped and shared by the members of a social group. Several theoretical extensions have been elaborated and particularly, the structural approach and the central core theory. These approaches sustain the arguments of a hierarchical organization of a social representation with a central core surrounded by peripheral zones. The central core is common and shared by the majority of the members of a given group, whereas the peripheral zones provide space for the individualization of the social knowledge. PURPOSE: The main goal of our study is to highlight the social representations of disease in health professionals (HP) and in non-health professionals (NHP). The group of HP has been differentiated into three subgroups: "medical doctors", "nurses" and "pharmacists", while that of NHP in two subgroups: those submitted to a "long period medical treatment" and those "without treatment". Our aim is to show that there are different social and professional Representations of disease. The professional representations are specific social representations related to professional contexts. We formulate the following assumptions (a) that the social representations of HP and NHP will be articulated around a common central core. Nevertheless, we expect to find specific peripheral elements related to professional status, based on different knowledge and a differentiated "practice"; (b) the HP should refer to more descriptive aspects of the disease and monitoring of patients, while (c) NHP should refer more to the experience of illness around emotional aspects. METHOD: Our sample is composed of 270 participants (135 HP and 135 HNP). Representations are measured by a free association task based on the target term: disease. The data have been submitted to prototypical and categorical analyses in agreement with the central core theory. RESULTS AND DISCUSSION: The results confirm that there is a common social representation of disease shared by the two groups, which refers essentially to suffering and pain. The analysis of each group brings to light two different registers: the one of the HP with more descriptive words referring to the nature and the illness's characteristics, and the other ones of the HNP with more words connected to emotions and referring to personal real experience of the illness. As expected, the social representation of the HP is referring to the "professional representations" of the disease, while the one for the HNP is linked to "practices" of an illness. An analysis of intra-group differences shows specificities for each of the questioned subgroups. In the HP, medical doctors focus on the diagnosis and consequences of the disease, pharmacists refer to the treatment of the disease and its management, while nurses focus on the treatment and on the relation while monitoring patients. In the NHP, people submitted to a "long period medical treatment" refer to the emotional aspects and to the consequences of the illness on their live, while those without treatment use more descriptive and formal terms. These results suggest to the PS to expand exchanges related to the disease in order to facilitate communication centered on taking care of the patient, considered in its wholeness and not only as an actual or potential patient. This is an important step in improving the health of the patient.

Phase II randomized study of whole-brain radiation therapy with or without concurrent temozolomide for brain metastases from breast cancer.

BACKGROUND: To improve the therapeutic index of whole-brain radiation therapy (WBRT) in the treatment of brain metastases (BM) from breast cancer, we investigated the efficacy and safety of WBRT combined with temozolomide (TMZ) in this population. PATIENTS AND METHODS: This phase II multicenter prospective randomized study included patients with newly diagnosed intraparenchymal BMs from breast cancer, unsuitable for surgery or radiosurgery. All patients received conformal WBRT (3 Gy × 10-30 Gy), with or without concomitant TMZ administered at a dosage of 75 mg/m(2)/day during the irradiation period. The primary end point was objective response rate (ORR) 6 weeks after the end of treatment, defined as a partial or complete response on systematic brain MRI (modified WHO criteria). Secondary end points were progression-free survival (PFS) and overall survival (OS), neurologic symptoms, and tolerability. RESULTS: Between February 2008 and November 2010, 100 patients were enrolled in the study (50 in the WBRT + TMZ arm, 50 in the WBRT arm). Median age was 55 years (29-79). Median follow-up was 9.4 months [1.0-68.1]. ORRs at 6 weeks were 36% in the WBRT arm and 30% in the WBRT + TMZ arm (NS). In the WBRT arm, median PFS was 7.4 months and median OS was 11.1 months. In the WBRT + TMZ arm, median PFS was 6.9 months and median OS was 9.4 months. Treatment was well tolerated in this arm: the most common ≥grade 2 acute toxicity was reversible lymphopenia. CONCLUSION: WBRT combined with TMZ did not significantly improve local control and survival in patients with BMs from breast cancer. CLINICALTRIALS.GOV: NCT00875355.

Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in advanced breast cancer.

BACKGROUND: Everolimus is an agent frequently associated with specific toxicities. Predictive markers of efficacy are needed to help define which patients could benefit from it. The goal of this exploratory study was to identify potential predictive biomarkers in the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activation pathway using primary tumor samples collected during the phase II tamoxifen plus everolimus (TAMRAD) trial. PATIENTS AND METHODS: Tumor tissues were collected retrospectively from the TAMRAD trial. Immunohistochemistry was carried out using specific antibodies directed toward proteins that result in mTORC1 activation [canonical phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR or alternative pathways]. DNA was extracted from the tumor tissue; mutation screening in the PIK3CA gene (exons 9 and 20) and the KRAS gene (exons 2 and 3) was first carried out using Sanger direct sequencing, and then completed by next-generation sequencing for PIK3CA. An exploratory analysis of everolimus efficacy in terms of a time-to-progression (TTP) increase was carried out in each biomarker subgroup (high versus low expression referring to the median percentage of marked cells). RESULTS: A total of 55 primary tumor samples from the TAMRAD trial­25 from the tamoxifen-alone group and 30 from the tamoxifen/everolimus group­were evaluated for biomarkers. The subgroups most likely to have an improvement in TTP with tamoxifen/everolimus therapy, compared with tamoxifen alone, were patients with high p4EBP1, low 4EBP1, low liver kinase B1, low pAkt, and low PI3K. Among the 45 samples screened for mutation status, nine samples (20%; 95% CI 9.6-34.6) had a PIK3CA mutation. KRAS mutation was observed in one patient. CONCLUSIONS: A positive correlation between late effectors of mTORC1 activation, a positive correlation between Akt-independent mTORC1 activation, and an inverse correlation between canonical PI3K/Akt/mTOR pathway and everolimus efficacy were observed in this exploratory analysis. However, these correlations need to be validated in larger studies before applying the findings to routine clinical practice.

Enhanced high-frequency molecular dynamics in the near-surface region of polystyrene thin films observed with ß-NMR.

ß-detected nuclear spin relaxation of (8)Li(+) has been used to probe the depth dependence of molecular dynamics in high- and low-molecular-weight deuterated polystyrene. The average nuclear spin-lattice relaxation rate, 1/T(avg)(1), is a measure of the spectral density of the polymer motion at the Larmor frequency (41 MHz at 6.55 T). In both samples, 1/T(avg)(1) is depth independent below ∼200 K but above this temperature it decreases approximately exponentially with distance from the free surface, returning to bulk behavior for depths greater than ∼10 nm. This is direct evidence for a region near the free surface with enhanced molecular dynamics compared with the bulk. The effective thickness of the surface region increases with increasing temperature and is finite even above the glass transition. These results present challenges for the current understanding of dynamics near the surface of polymer glasses.

Evaluation of PCR in the diagnosis of canine leishmaniasis in two different epidemiological regions: Campinas (SP) and Teresina (PI), Brazil.

SUMMARY Using the polymerase chain reaction (PCR) test for diagnosis of canine leishmaniasis has greater sensitivity and specificity than culture and visualization of the parasite. This study compares PCR for the diagnosis of the genus and species of Leishmania with serological techniques used for the control of canine visceral leishmaniasis (CVL) in Brazil, considering two regions. We analysed peripheral blood samples collected from 195 dogs in the Campinas (SP) and Teresina (PI) regions. ELISA was performed as a serological method and PCR was performed using specific primers for the genus Leishmania spp. and the species Leishmania chagasi. In Campinas, a greater sensitivity of PCR (88.24%) (P = 0.0455) compared to Teresina (14.71%) (P < 0.0001) was observed, and an agreement was observed for Cohen's kappa index (0.9096). Both PCR and ELISA showed discordance for sensitivity (Campinas 100%, Teresina 21.74%), specificity (Campinas 30.77%, Teresina 100%), positive predictive value (Campinas 68.97%, Teresina 100%), negative predictive value (Campinas 100%, Teresina 37.94%) and Cohen's kappa index (0.1238). This study confirms the importance of PCR in analysis of the canine reservoir, and as an effective method for the detection of active and recent infection.

Early impact of 13-valent pneumococcal conjugate vaccine on community-acquired pneumonia in children.

BACKGROUND: Pneumococcal serotypes 1, 3, 5, 7F, and 19A were the most implicated in community-acquired pneumonia (CAP) after implementation of 7-valent pneumococcal conjugate vaccine (PCV7). In France, the switch from PCV7 to 13-valent pneumococcal conjugate vaccine (PCV13) occurred in June 2010. An active surveillance network was set up to analyze the impact of PCV13 on CAP. METHODS: An observational prospective study performed in 8 pediatric emergency departments from June 2009 to May 2012 included all children between 1 month and 15 years of age with chest radiography-confirmed pneumonia. Three 1-year periods were defined: pre-PCV13, transitional, and post-PCV13. RESULTS: During the 3-year study period, among the 953 274 pediatric emergency visits, 5645 children with CAP were included. CAP with pleural effusion and documented pneumococcal CAP were diagnosed in 365 and 136 patients, respectively. Despite an increase (4.5%) in number of pediatric emergency visits, cases of CAP decreased by 16% (2060 to 1725) between pre- and post-PCV13 periods. The decrease reached 32% in infants in the same periods (757 to 516; P < .001). Between pre- and post-PCV13 periods, the proportion of CAP patients with a C-reactive protein level >120 mg/dL decreased from 41.3% to 29.7% (P < .001), the number of pleural effusion cases decreased by 53% (167 to 79; P < .001) and the number of pneumococcal CAP cases decreased by 63% (64 to 24; P = .002). The number of additional PCV13 serotypes identified decreased by 74% (27 to 7). CONCLUSIONS: Our data suggest a strong impact of PCV13 on CAP, pleural effusion, and documented pneumococcal pneumonia, particularly cases due to PCV13 serotypes.