Multi-omic machine learning predictor of breast cancer therapy response.

Breast cancers are complex ecosystems of malignant cells and the tumour microenvironment1. The composition of these tumour ecosystems and interactions within them contribute to responses to cytotoxic therapy2. Efforts to build response predictors have not incorporated this knowledge. We collected clinical, digital pathology, genomic and transcriptomic profiles of pre-treatment biopsies of breast tumours from 168 patients treated with chemotherapy with or without HER2 (encoded by ERBB2)-targeted therapy before surgery. Pathology end points (complete response or residual disease) at surgery3 were then correlated with multi-omic features in these diagnostic biopsies. Here we show that response to treatment is modulated by the pre-treated tumour ecosystem, and its multi-omics landscape can be integrated in predictive models using machine learning. The degree of residual disease following therapy is monotonically associated with pre-therapy features, including tumour mutational and copy number landscapes, tumour proliferation, immune infiltration and T cell dysfunction and exclusion. Combining these features into a multi-omic machine learning model predicted a pathological complete response in an external validation cohort (75 patients) with an area under the curve of 0.87. In conclusion, response to therapy is determined by the baseline characteristics of the totality of the tumour ecosystem captured through data integration and machine learning. This approach could be used to develop predictors for other cancers.

The relationship between interactive-imagery instructions and association memory.

Interactive imagery, one of the most effective strategies for remembering pairs of words, involves asking participants to form mental images during study. We tested the hypothesis that the visual image is, in fact, responsible for its memory benefit. Neither subjectively reported vividness (all experiments) nor objective imagery skill (experiments 1 and 3) could explain the benefit of interactive imagery for cued recall. Aphantasic participants, who self-identified little to no mental imagery, benefited from interactive-imagery instructions as much as controls (experiment 3). Imagery instructions did not improve memory for the constituent order of associations (AB versus BA), even when participants were told how to incorporate order within their images (experiments 1 and 2). Taken together, our results suggest that the visual format of images may not be responsible for the effectiveness of the interactive-imagery instruction and moreover, interactive imagery may not result in qualitatively different associative memories.

Comprehensive medication management by pharmacists via telehealth in rural primary care: is it feasible and effective?

INTRODUCTION: Patients with uncontrolled diabetes living in rural communities experience many challenges, including lack of access to needed medication management services. Telepharmacy has been identified as a promising approach for addressing this gap. This presentation describes early insights into the implementation of a Comprehensive Medication Management (CMM) service in seven rural primary care clinics in North Carolina and Arkansas (USA). The CMM service involved two pharmacists meeting remotely with patients in their homes to identify and resolve Medication Therapy Problems (MTPs). STUDY DESIGN: This exploratory mixed methods study uses a pre-post design. Data sources include surveys, qualitative interviews, administrative data, and medical records (eg MTPs, hemoglobin A1Cs) collected as part of the first 3 months of a 1-year implementation period. METHODS: Lessons learned were identified through qualitative interviews with six clinic liaisons, review of pharmacists' observations, and open-ended survey questions with clinic staff and providers. Early service effectiveness was informed by MTP resolution rates and changes in patients' A1C levels. RESULTS: Key insights centered on the perceived benefits of the service for patients and clinics, the importance of patient engagement, access to implementation strategies (eg workflows and technical assistance calls), and the need to adapt the CMM service and implementation strategies to local context. The MTP resolution rate averaged 88% across pharmacists. There was a significant decrease in A1Cs in participating patients as a result of the service. CONCLUSION: Although preliminary, these results support the value of a pharmacist-led medication optimization service through remote delivery for complex patients with uncontrolled diabetes.

Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients.

BACKGROUND: Previous studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings. METHODS: In this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, from patients (aged ≥18 years) with primary stage I-III breast cancer treated with neoadjuvant chemotherapy followed by surgery. We assessed the association between the continuous RCB score and the primary study outcome, event-free survival, using mixed-effects Cox models with the incorporation of random RCB and cohort effects to account for between-study heterogeneity, and stratification to account for differences in baseline hazard across cancer subtypes defined by hormone receptor status and HER2 status. The association was further evaluated within each breast cancer subtype in multivariable analyses incorporating random RCB and cohort effects and adjustments for age and pretreatment clinical T category, nodal status, and tumour grade. Kaplan-Meier estimates of event-free survival at 3, 5, and 10 years were computed for each RCB class within each subtype. FINDINGS: We analysed participant-level data from 5161 patients treated with neoadjuvant chemotherapy between Sept 12, 1994, and Feb 11, 2019. Median age was 49 years (IQR 20-80). 1164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0-186]). RCB score was prognostic within each breast cancer subtype, with higher RCB score significantly associated with worse event-free survival. The univariable hazard ratio (HR) associated with one unit increase in RCB ranged from 1·55 (95% CI 1·41-1·71) for hormone receptor-positive, HER2-negative patients to 2·16 (1·79-2·61) for the hormone receptor-negative, HER2-positive group (with or without HER2-targeted therapy; p<0·0001 for all subtypes). RCB score remained prognostic for event-free survival in multivariable models adjusted for age, grade, T category, and nodal status at baseline: the adjusted HR ranged from 1·52 (1·36-1·69) in the hormone receptor-positive, HER2-negative group to 2·09 (1·73-2·53) in the hormone receptor-negative, HER2-positive group (p<0·0001 for all subtypes). INTERPRETATION: RCB score and class were independently prognostic in all subtypes of breast cancer, and generalisable to multiple practice settings. Although variability in hormone receptor subtype definitions and treatment across patients are likely to affect prognostic performance, the association we observed between RCB and a patient's residual risk suggests that prospective evaluation of RCB could be considered to become part of standard pathology reporting after neoadjuvant therapy. FUNDING: National Cancer Institute at the US National Institutes of Health.

Comparing race and ethnicity across safety-net and non-safety net practices pre- and post-an HIV screening alert.

CONTEXT: Societal and economic burdens of human immunodeficiency virus (HIV) continue to grow, even as treatments and prevention for this disease becomes more readily available and efficacious. HIV screening is more likely to be performed in minority (including Black) patient populations compared to whites. The likelihood of getting screened also depends on primary care practice attributes. OBJECTIVE: Evaluate HIV screening demographics by safety-net and non-safety net practices. STUDY DESIGN and ANALYSIS: Pre-post analysis. SETTING: Atrium Health is a non-profit, vertically integrated healthcare system with approximately 16 million patient encounters per year across the Southeast US. POPULATION STUDIED: Twelve primary care practices, including four safety-net practices serving predominantly Medicaid and uninsured patients, with over 115,00 patients between the ages of 18 and 64 were selected for the educational intervention. INTERVENTION/INSTRUMENT: A system-wide electronic medical record alert prompting HIV screening was implemented in October 2017 targeting adults between 18-64 years old. In addition to the system alert, a provider peer-to-peer educational program detailing HIV disease epidemiology, screening recommendations, and algorithms to guide screening efforts was developed. OUTCOME MEASURES: HIV screenings. RESULTS: From October 2016- April 2017, 3,413 patients were screened for HIV at the twelve participating primary care practices. Immediately after the HIV alert activation, from October 2017 - April 2018, 6,256 patients were screened, resulting in an 83% increase in screening. However, increases were different based on practice type, race and ethnicity. Black patients in safety net clinics had higher screening rates prior to the alert and showed less of an increase in screening (37%) compared to whites (102%) after the alert was activated. Hispanic/Latino patients showed similar increases at both safety net (99%) and non-safety net (108%) practices. Both Black and white patients showed larger increases of 99% and 139% in non-safety net clinics. Chi-squared analysis comparing the percentage of patients screened during these time periods was significantly different (p=0.001). CONCLUSION: While race and practice characteristics influence the likelihood of HIV screening, EMR modifications and provider education can significantly enhance screening and care for patients with HIV regardless of race and practice type.

Application of Counter-wound Multi-arm Spirals in HTS Resonator Design.

Significant sensitivity improvements have been achieved by utilizing high temperature superconducting (HTS) resonators in nuclear magnetic resonance (NMR) probes. Many nuclei such as 13C benefit from strong excitation fields which cannot be produced by traditional HTS resonator designs. We investigate the use of double-sided, counter-wound multi-arm spiral HTS resonators with the aim of increasing the excitation field at the required nuclear Larmor frequency for 13C. When compared to double-sided, counter-wound spiral resonators with similar geometry, simulations indicate that the multi-arm spiral version develops a more uniform current distribution. Preliminary tests of a two-arm resonator indicate that it may produce a stronger excitation field.

Pathological features of 11,337 patients with primary ductal carcinoma in situ (DCIS) and subsequent events: results from the UK Sloane Project.

BACKGROUND: The Sloane audit compares screen-detected ductal carcinoma in situ (DCIS) pathology with subsequent management and outcomes. METHODS: This was a national, prospective cohort study of DCIS diagnosed during 2003-2012. RESULTS: Among 11,337 patients, 7204 (64%) had high-grade DCIS. Over time, the proportion of high-grade disease increased (from 60 to 65%), low-grade DCIS decreased (from 10 to 6%) and mean size increased (from 21.4 to 24.1 mm). Mastectomy was more common for high-grade (36%) than for low-grade DCIS (15%). Few (6%) patients treated with breast-conserving surgery (BCS) had a surgical margin <1 mm. Of the 9191 women diagnosed in England (median follow-up 9.4 years), 7% developed DCIS or invasive malignancy in the ipsilateral and 5% in the contralateral breast. The commonest ipsilateral event was invasive carcinoma (n = 413), median time 62 months, followed by DCIS (n = 225), at median 37 months. Radiotherapy (RT) was most protective against recurrence for high-grade DCIS (3.2% for high-grade DCIS with RT compared to 6.9% without, compared with 2.3 and 3.0%, respectively, for low/intermediate-grade DCIS). Ipsilateral DCIS events lessened after 5 years, while the risk of ipsilateral invasive cancer remained consistent to beyond 10 years. CONCLUSION: DCIS pathology informs patient management and highlights the need for prolonged follow-up of screen-detected DCIS.

Progress Towards a Higher Sensitivity 13C-Optimized 1.5 mm HTS NMR Probe.

Nuclear magnetic resonance (NMR) probes using thin-film high temperature superconducting (HTS) resonators offer high sensitivity and are particularly suitable for small-sample applications. We are developing an improved 1.5 mm HTS NMR probe designed for operation at 14.1 T and optimized for 13C detection. The total sample volume is about 35 µL and the active sample volume is 20 µL. The probe employs HTS resonators for 13C and 1H transmission and detection and the 2H lock. We examine the interactions of multiple superconducting resonators and normal metal tuning loops on coil resonance frequency and probe sensitivity. We test a recently introduced 13C resonator design, engineered to significantly increase 13C detection sensitivity over previous all-HTS probes. At zero field, we observe a 13C quality factor of 6000 which is several times higher than previous resonators. In this work the coil design considerations and probe build-out procedure are discussed.

Classifying intervention modifications in the community pharmacy context: A demonstration study.

OBJECTIVES: The objectives of this study were to apply the Stirman and colleagues' framework to identify modifications made to a motivational interviewing (MI)-based intervention for medication nonadherence and to determine whether the locally modified intervention affected expected patient medication adherence outcomes in community pharmacies. METHODS: Pharmacists at 4 pharmacies were trained to provide a brief MI intervention to 50 patients per pharmacy who were nonadherent to antihypertensive medications. The training included a 3-hour online course in MI and in-pharmacy training on patient identification and documentation. Semistructured interviews were conducted to determine modifications to the patient identification processes, MI interventions, and documentation of interventions. Directed content analysis was guided by the Stirman and colleagues' framework. Preintervention and 6 months postintervention adherence rates for the patients who received the intervention were calculated. Paired samples t tests were used to assess the impact of the intervention on adherence rates. RESULTS: Modifications were made to the context of the intervention (e.g., via telephone instead of in-pharmacy). Additionally, content modifications included "loosening the structure" (e.g., reordering intervention steps), "drifting or departing" (e.g., too busy to attempt), "adding elements" (e.g., reminder cards), and "repeating elements" (e.g., patient identification). There were statistically significant improvements in adherence from preintervention to 6 months postintervention (74.1% to 84.5%; P < 0.05) at each pharmacy regardless of the modifications applied. CONCLUSION: Modifications made during intervention implementation were classified using Stirman and colleagues' framework. Despite the modifications, adherence rates improved and were consistent with expectations based on prior studies of similar interventions. These findings support previous implementation research on adaptability and suggest that the ability to tailor, modify, or refine an intervention to meet the needs of the provider or setting may allow for intervention success. Future research on the impact of specific modifications will help determine which are detrimental or beneficial to patient outcomes and sustainability of services.

Development and implementation of a collaboration between a patient-centered medical home and community pharmacy.

OBJECTIVES: This study aimed to describe the development and implementation strategies used in the collaboration between a patient-centered medical home (PCMH) and a grocery pharmacy chain and to evaluate the effectiveness of a community pharmacist's clinical integration in reducing hemoglobin A1c levels at clinic and patient levels. SETTING: The Kroger Co and Catholic Health Initiative St. Vincent. PRACTICE DESCRIPTION: The Kroger Co is a large grocery store that operates 27 pharmacies in the state of Arkansas, with 20 locations in the central Arkansas area. PCMH is part of a large health system in central Arkansas with 10 primary-care clinics in the area. PRACTICE INNOVATION: With the transition to value-based payment models, pharmacists are being utilized in settings outside of the pharmacy. This project demonstrates a partnership between a community pharmacy and PCMH. The community pharmacist spent 20 h/week in the PCMH providing medication therapy and disease state management services. Services were focused on patients with uncontrolled diabetes. EVALUATION: Descriptive statistics were used to describe the distribution of the pharmacists' time. A patient-level pre-post analysis of the mean changes in hemoglobin A1c (HbA1c) was conducted for patients who interacted directly with the pharmacist. A clinic-level analysis was conducted to evaluate changes in HbA1c compared to that in a nonequivalent control group using a standard quality measure. RESULTS: In total, 312 individual patients interacted with the pharmacist. Of those patients, 228 had diabetes. A total of 111 patients underwent pre-post HbA1c analysis. In those patients, there was a statistically significant reduction in mean HbA1c . There was no difference in clinic-level results between the intervention and control locations. CONCLUSION: Collaboration between a community pharmacy and PCMH is feasible and may improve patient care. Future research should include pharmacy-based visits and development of a process for improved communication.

Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours.

BACKGROUND: The risk of recurrence for endocrine-treated breast cancer patients persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate; previous efforts have been limited to in-vitro or in-vivo approaches. In this study, sequential tumour samples from patients receiving extended neoadjuvant aromatase inhibitor therapy were characterised as a novel clinical model. METHODS: Consecutive tumour samples from 62 patients undergoing extended (4-45 months) neoadjuvant aromatase inhibitor therapy with letrozole were subjected to transcriptomic and proteomic analysis, representing before (≤ 0), early (13-120 days), and long-term (> 120 days) neoadjuvant aromatase inhibitor therapy with letrozole. Patients with at least a 40% initial reduction in tumour size by 4 months of treatment were included. Of these, 42 patients with no subsequent progression were classified as "dormant", and the remaining 20 patients as "acquired resistant". RESULTS: Changes in gene expression in dormant tumours begin early and become more pronounced at later time points. Therapy-induced changes in resistant tumours were common features of treatment, rather than being specific to the resistant phenotype. Comparative analysis of long-term treated dormant and resistant tumours highlighted changes in epigenetics pathways including DNA methylation and histone acetylation. The DNA methylation marks 5-methylcytosine and 5-hydroxymethylcytosine were significantly reduced in resistant tumours compared with dormant tissues after extended letrozole treatment. CONCLUSIONS: This is the first patient-matched gene expression study investigating long-term aromatase inhibitor-induced dormancy and acquired resistance in breast cancer. Dormant tumours continue to change during treatment whereas acquired resistant tumours more closely resemble their diagnostic samples. Global loss of DNA methylation was observed in resistant tumours under extended treatment. Epigenetic alterations may lead to escape from dormancy and drive acquired resistance in a subset of patients, supporting a potential role for therapy targeted at these epigenetic alterations in the management of resistance to oestrogen deprivation therapy.

Molecular apocrine tumours in EORTC 10994/BIG 1-00 phase III study: pathological response after neoadjuvant chemotherapy and clinical outcomes.

BACKGROUND: We explored, within the EORTC10994 study, the outcomes for patients with molecular apocrine (MA) breast cancer, and defined immunohistochemistry (IHC) as androgen-receptor (AR) positive, oestrogen (ER) and progesterone (PR) negative. We also assessed the concordance between IHC and gene expression arrays (GEA) in the identification of MA cancers. METHODS: Centrally assessed biopsies for AR, ER, PR, HER2 and Ki67 by IHC were classified into six subtypes: MA, triple-negative (TN) basal-like, luminal A, luminal B HER2 negative, luminal B HER2 positive and "other". The two main objectives were the pCR rates and survival outcomes in the overall MA subtype (and further divided by HER2 status) and the remaining five subtypes. RESULTS: IHC subtyping was obtained in 846 eligible patients. Ninety-three (11%) tumours were classified as the MA subtype. Both IHC and GEA data were available for 64 patients. In this subset, IHC concordance was 88.3% in identifying MA tumours compared with GEA. Within the MA subtype, pCR was observed in 33.3% of the patients (95% CI: 29.4-43.9) and the 5-year recurrence-free interval was 59.2% (95% CI: 48.2-68.6). Patients with MA and TN basal-like tumours have lower survival outcomes. CONCLUSIONS: Irrespective of their HER2 status, the prognosis for MA tumours remains poor and adjuvant trials evaluating anti-androgens should be considered.

Pharmacist-provided services and community pharmacist integration into a patient-centered medical home: A qualitative study of primary care clinic staff perceptions.

OBJECTIVES: To describe patient-centered medical home (PCMH) staff members' views toward community pharmacist involvement in patient care within the PCMH and to identify areas in which pharmacist-provided services can improve the quality of care in their clinics. DESIGN: Qualitative semistructured interview study. SETTING: One primary care clinic. PARTICIPANTS: Multidisciplinary clinic staff members. OUTCOME MEASURES: Views of staff toward implementing a community pharmacist into their clinic and top pharmacist services to help improve medication management within the clinic. RESULTS: A total of 14 staff members of the clinic participated in the study. Participants included physicians, clinical staff members such as registered nurse assistants, licensed practical nurses, and medical assistants, and clinic management. Key themes included the following: the clinic was open to implementing pharmacy services; the providers would be very receptive to pharmacist recommendations; the clinic is willing to try different pharmacist integration models to see what works best within the workflow; the pharmacist must be readily available for consultation; the pharmacist should hold an introductory meeting with the clinic; opinions vary on the best timing of pharmacist appointments with patients; and ideas vary about the best location for pharmacist consultations. The top 5 pharmacist services mentioned by participants included chronic condition management, medication reconciliation training, Beers List education, diabetes education, and adherence counseling. CONCLUSION: Primary care clinic staff support the integration of pharmacy services. Further research is needed to apply the results to other clinics and to identify barriers and opportunities in the implementation process.

Central pathology review with two-stage quality assurance for pathological response after neoadjuvant chemotherapy in the ARTemis Trial.

The ARTemis Trial tested standard neoadjuvant chemotherapy±bevacizumab in the treatment of HER2-negative early breast cancer. We compare data from central pathology review with report review and also the reporting behavior of the two central pathologists. Eight hundred women with HER2-negative early invasive breast cancer were recruited. Response to chemotherapy was assessed from local pathology reports for pathological complete response in breast and axillary lymph nodes. Sections from the original core biopsy and surgical excision were centrally reviewed by one of two trial pathologists blinded to the local pathology reports. Pathologists recorded response to chemotherapy descriptively and also calculated residual cancer burden. 10% of cases were double-reported to compare the central pathologists' reporting behavior. Full sample retrieval was obtained for 681 of the 781 patients (87%) who underwent surgery within the trial and were evaluable for pathological complete response. Four hundred and eighty-three (71%) were assessed by JSJT, and 198 (29%) were assessed by EP. Residual cancer burden calculations were possible in 587/681 (86%) of the centrally reviewed patients, as 94/681 (14%) had positive sentinel nodes removed before neoadjuvant chemotherapy invalidating residual cancer burden scoring. Good concordance was found between the two pathologists for residual cancer burden classes within the 65-patient quality assurance exercise (kappa 0.63 (95% CI: 0.57-0.69)). Similar results were obtained for the between-treatment arm comparison both from the report review and the central pathology review. For pathological complete response, report review was as good as central pathology review but for minimal residual disease, report review overestimated the extent of residual disease. In the ARTemis Trial central pathology review added little in the determination of pathological complete response but had a role in evaluating low levels of residual disease. Calculation of residual cancer burden was a simple and reproducible method of quantifying response to neoadjuvant chemotherapy as demonstrated by performance comparison of the two pathologists.

Surgical Upstaging Rates for Vacuum Assisted Biopsy Proven DCIS: Implications for Active Surveillance Trials.

PURPOSE: This study was designed to determine invasive cancer upstaging rates at surgical excision following vacuum-assisted biopsy of ductal carcinoma in situ (DCIS) among women meeting eligibility for active surveillance trials. METHODS: Patients with vacuum-assisted, biopsy-proven DCIS at a single center from 2008 to 2015 were retrospectively reviewed. Imaging and pathology reports were interrogated for the imaging appearance, tumor grade, hormone receptor status, and presence of comedonecrosis. Subsequent surgical reports were reviewed for upstaging to invasive disease. Cases were classified by eligibility criteria for the COMET, LORIS, and LORD DCIS active surveillance trials. RESULTS: Of 307 DCIS diagnoses, 15 (5%) were low, 95 (31%) intermediate, and 197 (64%) high nuclear grade. The overall upstage rate to invasive disease was 17% (53/307). Eighty-one patients were eligible for the COMET Trial, 74 for the LORIS trial, and 10 for the LORD Trial, although LORIS trial eligibility also included real-time, multiple central pathology review, including elements not routinely reported. The upstaging rates to invasive disease were 6% (5/81), 7% (5/74), and 10% (1/10) for the COMET, LORIS, and LORD trials, respectively. Among upstaged cancers (n = 5), four tumors were Stage IA invasive ductal carcinoma and one was Stage IIA invasive lobular carcinoma; all were node-negative. CONCLUSIONS: DCIS upstaging rates in women eligible for active surveillance trials are low (6-10%), and in this series, all those with invasive disease were early-stage, node-negative. The careful patient selection for DCIS active surveillance trials has a low risk of missing occult invasive cancer and additional studies will determine clinical outcomes.

Breast conservation in ductal carcinoma in situ (DCIS): what defines optimal margins?

The introduction of mammographic screening has resulted in a rise in the detection rate of ductal carcinoma in situ (DCIS), currently accounting for one-fifth of screen-detected breast cancers. Although 60-70% of DCIS are treated with breast-conserving surgery (BCS) with or without radiotherapy, the frequency of subsequent surgery to re-excise positive margins in order to reduce the probability of recurrences remains high. DCIS recurrence is associated not only with financial, health and psychological implications; approximately half these recurrences are invasive disease. An appropriate margin width for patients undergoing BCS for invasive breast cancer has been largely agreed. Although there is a perception that such recommendations may be applicable to DCIS, major differences exist which may affect this application. Importantly, DCIS patients often do not receive systemic adjuvant (endocrine) therapy and not all receive radiotherapy in routine practice. There is evidence that wide margins (i.e. >10 mm) confer better protection against recurrence than positive (i.e. 0 mm) margins; however, there remains a debate concerning the optimum margin width between 0 and 10 mm. Previous studies have demonstrated that radiation therapy may not compensate for lack of re-excision in those patients with positive or close margins, while wide margins will inevitably compromise cosmesis and patients' body image perception. This review aims to address the clinical question of the minimal margin width in DCIS treated with BCS that is associated with the lowest recurrence rate and when, therefore, further surgical intervention for re-excision can be safely avoided. A range of clinical circumstances that might affect this are considered.

Anti-ictogenic and antiepileptogenic properties of perampanel in mature and immature rats.

OBJECTIVE: Perampanel (PER) is a selective noncompetitive antagonist at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, the first of its class approved for the adjunctive treatment of partial onset seizures and generalized seizures. This study explored anti-ictogenic and antiepileptogenic effects of PER in rats at different stages of development. METHODS: Using a rapid kindling model in postnatal day 14 (P14), P21, P28, and P60 rats, we studied two doses of PER: 1 and 2 mg/kg injected intraperitoneally 30 min before afterdischarge assessment. We also assessed blood and brain concentrations of PER 30 min after the injection. RESULTS: PER 2 mg/kg significantly increased the afterdischarge threshold (ADT) at all ages, whereas PER at 1 mg/kg increased ADT only in P21 rats. PER 2 mg/kg also shortened the afterdischarge duration in P14 and P28 rats. PER increased the number of stimulations required to achieve a stage 4-5 seizure in a dose-dependent manner in P14 and P21 rats, with almost complete elimination of stage 4-5 seizures. At P28, only PER 2 mg/kg increased the number of stimulations required to develop a stage 4-5 seizure. In contrast, PER had no effect on the number of stage 4-5 seizures at P60. We did not observed any age-dependent significant difference in the serum and brain levels of PER 30 min after the injection. SIGNIFICANCE: PER exerted anti-ictogenic effects from P14 to P60 independent of brain maturation. PER also exhibited antiepileptogenic effects with a stronger effect in the younger animals.

Outcomes of patients with inflammatory breast cancer treated by breast-conserving surgery.

PURPOSE: Inflammatory breast cancer (IBC) is rare and associated with a poor prognosis. Following neoadjuvant chemotherapy or endocrine therapy, the multidisciplinary team selected a small number of patients for breast-conservation therapy (BCT). The aim of this study was to determine the outcome of IBC patients treated with BCT in Edinburgh. METHODS: Between January 1999 and December 2013, thirty-five women with IBC were treated by BCT. The median follow-up was 80 months. RESULTS: The 5-year actuarial survival for the 35 patients was 70.3 %. Median survival for 20 neoadjuvant chemotherapy patients was 12.9 years (95 % CI 7.6, 18.1), and for 14 patient neoadjuvant endocrine therapy patients, it was 11.8 years (95 % CI 1.1, 22.6) (p = 0.34). Five patients developed locoregional recurrence (LRR) between 11 and 72 months after BCT (median 37 months). Three had breast only recurrence, one patient had both breast and axillary recurrence, and one developed axillary recurrence. The 5-year LR-free survival was 87.5 % (95 % CI 76.0, 99.0). In 4 of the 5 patients with LRR, systemic metastases were diagnosed within 6 months and survival post-LRR in these 4 patients was short. CONCLUSION: IBC is not an absolute contraindication to BCT. LRR in patients after BCT appears part of widespread recurrent disease rather than inadequate local treatment. Multicentre data should be collected to confirm that women with IBC who have a good response to systemic therapy may be offered BCT in the knowledge that in a larger series our observations are confirmed.

Is Bondage and Discipline, Dominance and Submission, and Sadomasochism Recreational Leisure? A Descriptive Exploratory Investigation.

INTRODUCTION: Recent studies have suggested that, in contrast to traditional psychopathologic explanations, bondage and discipline, dominance and submission, and sadomasochism (BDSM) could be understood as recreational leisure. However, the theoretical framing of BDSM as potential leisure has not been empirically explored. AIM: To conduct an initial empirical exploration to determine whether BDSM experience fits established characteristics of recreational leisure. METHODS: A convenience sample of BDSM participants (N = 935) completed an online survey (9 demographic questions and 17 leisure questions) that assessed BDSM experience according to important attributes of leisure. Responses also were assessed and statistically compared as being primarily casual or serious leisure according to general BDSM identities (ie, dominants vs submissives vs switches). MAIN OUTCOME MEASURES: BDSM experiences were assessed as a form of potential leisure. RESULTS: Most BDSM experiences met leisure criteria. Participants reported that "most of the time or nearly always" BDSM was associated with a sense of personal freedom (89.7% of participants), pleasure or enjoyment (98.5%), sense of adventure (90.7%), use of personal skills (90.8%), relaxation or decreased stress (91.4%), self-expression or exploration (90.6%), and positive emotions (96.6%). BDSM seemed to function as primarily serious, rather than casual, leisure, but important statistical differences were observed based on specific BDSM identities. CONCLUSION: A leisure science perspective could be valuable to researchers and clinicians in reinterpreting the wide range of diverse BDSM motivations and practices.

Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial.

BACKGROUND: The ARTemis trial was developed to assess the efficacy and safety of adding bevacizumab to standard neoadjuvant chemotherapy in HER2-negative early breast cancer. METHODS: In this randomised, open-label, phase 3 trial, we enrolled women (≥18 years) with newly diagnosed HER2-negative early invasive breast cancer (radiological tumour size >20 mm, with or without axillary involvement), at 66 centres in the UK. Patients were randomly assigned via a central computerised minimisation procedure to three cycles of docetaxel (100 mg/m(2) once every 21 days) followed by three cycles of fluorouracil (500 mg/m(2)), epirubicin (100 mg/m(2)), and cyclophosphamide (500 mg/m(2)) once every 21 days (D-FEC), without or with four cycles of bevacizumab (15 mg/kg) (Bev+D-FEC). The primary endpoint was pathological complete response, defined as the absence of invasive disease in the breast and axillary lymph nodes, analysed by intention to treat. The trial has completed and follow-up is ongoing. This trial is registered with EudraCT (2008-002322-11), ISRCTN (68502941), and ClinicalTrials.gov (NCT01093235). FINDINGS: Between May 7, 2009, and Jan 9, 2013, we randomly allocated 800 participants to D-FEC (n=401) and Bev+D-FEC (n=399). 781 patients were available for the primary endpoint analysis. Significantly more patients in the bevacizumab group achieved a pathological complete response compared with those treated with chemotherapy alone: 87 (22%, 95% CI 18-27) of 388 patients in the Bev+D-FEC group compared with 66 (17%, 13-21) of 393 patients in the D-FEC group (p=0·03). Grade 3 and 4 toxicities were reported at expected levels in both groups, although more patients had grade 4 neutropenia in the Bev+D-FEC group than in the D-FEC group (85 [22%] vs 68 [17%]). INTERPRETATION: Addition of four cycles of bevacizumab to D-FEC in HER2-negative early breast cancer significantly improved pathological complete response. However, whether the improvement in pathological complete response will lead to improved disease-free and overall survival outcomes is unknown and will be reported after longer follow-up. Meta-analysis of available neoadjuvant trials is likely to be the only way to define subgroups of early breast cancer that would have clinically significant long-term benefit from bevacizumab treatment. FUNDING: Cancer Research UK, Roche, Sanofi-Aventis.