IMpassion132 double-blind randomised phase III trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer.

BACKGROUND: Immune checkpoint inhibitors improve the efficacy of first-line chemotherapy for patients with programmed death-ligand 1 (PD-L1)-positive unresectable locally advanced/metastatic triple-negative breast cancer (aTNBC), but randomised data in rapidly relapsing aTNBC are scarce. PATIENTS AND METHODS: IMpassion132 (NCT03371017) enrolled patients with aTNBC relapsing <12 months after last chemotherapy dose (anthracycline and taxane required) or surgery for early TNBC. PD-L1 status was centrally assessed using SP142 before randomisation. Initially patients were enrolled irrespective of PD-L1 status. From August 2019, enrolment was restricted to PD-L1-positive (tumour immune cell ≥1%) aTNBC. Patients were randomised 1:1 to placebo or atezolizumab 1200 mg every 21 days with investigator-selected chemotherapy until disease progression or unacceptable toxicity. Stratification factors were chemotherapy regimen (carboplatin plus gemcitabine or capecitabine monotherapy), visceral (lung and/or liver) metastases and (initially) PD-L1 status. The primary endpoint was overall survival (OS), tested hierarchically in patients with PD-L1-positive tumours and then, if positive, in the modified intent-to-treat (mITT) population (all-comer patients randomised pre-August 2019). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. RESULTS: Among 354 patients with rapidly relapsing PD-L1-positive aTNBC, 68% had a disease-free interval of <6 months and 73% received carboplatin/gemcitabine. The OS hazard ratio was 0.93 (95% confidence interval 0.73-1.20, P = 0.59; median 11.2 months with placebo versus 12.1 months with atezolizumab). mITT and subgroup results were consistent. Median PFS was 4 months across treatment arms and populations. ORRs were 28% with placebo versus 40% with atezolizumab. Adverse events (predominantly haematological) were similar between arms and as expected with atezolizumab plus carboplatin/gemcitabine or capecitabine following recent chemotherapy exposure. CONCLUSIONS: OS, which is dismal in patients with TNBC relapsing within <12 months, was not improved by adding atezolizumab to chemotherapy. A biology-based definition of intrinsic resistance to immunotherapy in aTNBC is urgently needed to develop novel therapies for these patients in next-generation clinical trials.

Noise Transfer Approach to GKP Quantum Circuits.

The choice between the Schrödinger and Heisenberg pictures can significantly impact the computational resources needed to solve a problem, even though they are equivalent formulations of quantum mechanics. Here, we present a method for analysing Bosonic quantum circuits based on the Heisenberg picture which allows, under certain conditions, a useful factoring of the evolution into signal and noise contributions, similar way to what can be achieved with classical communication systems. We provide examples which suggest that this approach may be particularly useful in analysing quantum computing systems based on the Gottesman-Kitaev-Preskill (GKP) qubits.

Clustering of comorbidities and associated outcomes in people with osteoarthritis - A UK Clinical Practice Research Datalink study.

OBJECTIVE: To examine the clusters of chronic conditions present in people with osteoarthritis and the associated risk factors and health outcomes. METHODS: Clinical Practice Research Datalink (CPRD) GOLD was used to identify people diagnosed with incident osteoarthritis (n = 221,807) between 1997 and 2017 and age (±2 years), gender, and practice matched controls (no osteoarthritis, n = 221,807) from UK primary care. Clustering of people was examined for 49 conditions using latent class analysis. The associations between cluster membership and covariates were quantified by odds ratios (OR) using multinomial logistic regression. General practice (GP) consultations, hospitalisations, and all-cause mortality rates were compared across the clusters identified at the time of first diagnosis of osteoarthritis (index date). RESULTS: In both groups, conditions largely grouped around five clusters: relatively healthy; cardiovascular (CV), musculoskeletal-mental health (MSK-MH), CV-musculoskeletal (CV-MSK) and metabolic (MB). In the osteoarthritis group, compared to the relatively healthy cluster, strong associations were seen for 1) age with all clusters; 2) women with the MB cluster (OR 5.55: 5.14-5.99); 3) obesity with the CV-MSK (OR 2.11: 2.03-2.20) and CV clusters (OR 2.03: 1.97-2.09). The CV-MSK cluster in the osteoarthritis group had the highest number of GP consultations and hospitalisations, and the mortality risk was 2.45 (2.33-2.58) times higher compared to the relatively healthy cluster. CONCLUSIONS: Of the five identified clusters, CV-MSK, CV, and MSK-MH are more common in OA and CV-MSK cluster had higher health utilisation. Further research is warranted to better understand the mechanistic pathways and clinical implications.

Synovitis and bone marrow lesions associate with symptoms and radiographic progression in hand osteoarthritis: a systematic review and meta-analysis of observational studies.

AIMS: To systematically review observational studies for the association between features detected on ultrasound (US) and magnetic resonance imaging (MRI) and, symptoms, signs and radiographic progression of hand osteoarthritis (OA). METHODS: Medline, Web of Science, EMBASE, CINAHL and AMED were searched from inception to 14th January 2020 to identify relevant studies. Quality of studies was assessed using the Newcastle-Ottawa scales and data were extracted. Odds ratios (OR) and linear regression coefficients and 95% confidence intervals (CI) were pooled using the random-effects model (METAN package, Stata v16.1). Heterogeneity and publication bias were assessed. RESULTS: Thirty-two studies using US and MRI comprising 1,350 and 638 participants respectively were included. While only grey-scale synovitis (GSS) associated with AUSCAN-pain (pooled Regression coefficient (95% CI): 0.46 (0.13-0.79); 0-20 scale for AUSCAN-pain), US-detected osteophytes, GSS and power Doppler (PD) [pooled ORs (95% CI): 2.68(2.16-3.33), 2.38(1.74-3.26) and 2.04 (1.45-2.88)] as well as MRI-detected bone marrow lesions (BMLs), synovitis, osteophytes, and central bone erosions (CBEs) associated with joint tenderness [pooled ORs (95% CI): 2.59(2.12-3.18), 2.17(1.85-2.54), 2.15(1.55-2.99), and 2.41 (1.45-4.02)] respectively. US-detected GSS and PD associated with radiographic progression of CBEs [pooled ORs 5.37, 5.08], osteophytes [pooled ORs 5.17, 6.45], and joint space narrowing (pooled ORs 4.28, 4.36) whilst MRI-detected synovitis and BMLs associated with increasing KL grades with pooled ORs 2.92, 2.54 respectively. CONCLUSIONS: US and MRI-detected structural and inflammatory changes associate with tenderness, whilst articular inflammation and subchondral bone damage associate with radiographic hand OA progression. There was inconsistent relationship between these changes and pain.

Efficacy of group intervention on tobacco cessation among male employees in health-care setting: A randomized controlled trial.

BACKGROUND: The tobacco epidemic is one of the biggest public health threats the world has ever faced. World Health Organization has estimated that tobacco use (smoking and smokeless) is currently responsible for the death of about 7 million people across the world each year. The objective of the study was not only to find the effect of group intervention on tobacco cessation but also to describe certain epidemiological factors associated with tobacco cessation and make suitable recommendations to tackle this epidemic. METHODS: A randomized controlled trial was carried out among male employees who were tobacco users in health-care setting in Western Maharashtra. In the study, 60 subjects each in intervention and control arm were taken. Pretested validated questionnaires were used for the study. The intervention comprised of two sessions delivered 5 weeks apart. Control arm received self-help material (Booklet) immediately after baseline data collection. The outcomes were measured using structured interview schedule. The data were analyzed using SPSS, version 20. RESULTS: Overall, 13.3% of the study subjects had quit tobacco use post intervention. In the intervention group 21.7% of the participants had quit tobacco since past one month and 5% in the control group (relative risk (RR) = 4.33). Low to moderate nicotine dependence (p = 0.023, RR = 6.46) and stage of contemplation (p = 0.018) were found to be important predictors of abstinence. CONCLUSION: Community-based group intervention for tobacco cessation is the way forward to tackle the tobacco epidemic.

Trends in incidence and prevalence of osteoarthritis in the United Kingdom: findings from the Clinical Practice Research Datalink (CPRD).

OBJECTIVE: This study aimed to explore the incidence and prevalence of OA in the UK in 2017 and their trends from 1997 to 2017 using a large nationally representative primary care database. DESIGN: The UK Clinical Practice Research Datalink (CPRD) comprising data on nearly 17.5 million patients was used for the study. The incidence and prevalence of general practitioner diagnosed OA over a 20 years period (1997-2017) were estimated and age-sex and length of data contribution standardized using the 2017 CPRD population structure. Cohort effects were examined through Age-period-cohort analysis. RESULTS: During 1997-2017, there were 494,716 incident OA cases aged ≥20 years. The standardised incidence of any OA in 2017 was 6.8 per 1000 person-years (95% CI 6.7 to 6.9) and prevalence was 10.7% (95% CI 10.7-10.8%). Both incidence and prevalence were higher in women than men. The incidence of any-OA decreased gradually in the past 20 years at an annual rate of -1.6% (95%CI -2.0 to -1.1%), and the reduction speeded up for people born after 1960. The prevalence of any-OA increased gradually at an annual rate of 1.4% (95% CI 1.3-1.6%). Although the prevalence was highest in Scotland and Northern Ireland, incidence was highest in the East Midlands. Both incidence and prevalence reported highest in the knee followed by hip, wrist/hand and ankle/foot. CONCLUSION: In the UK approximately one in 10 adults have symptomatic clinically diagnosed OA, the knee being the commonest. While prevalence has increased and become static after 2008, incidence is slowly declining. Further research is required to understand these changes.

Avoiding over- and undertreatment in patients with resected node-positive breast cancer with the use of gene expression signatures: are we there yet?

Prediction of benefit from adjuvant chemotherapy following resection of early breast cancer and, as a result, proper selection of candidates remains an elusive goal since the relative magnitude of benefit is the same regardless of the presence of clinicopathologic factors. Multiple studies, including randomized trials, establish the role of certain gene expression signatures in node-negative disease since they predict the risk of breast cancer relapse being so low that adjuvant chemotherapy can be omitted. In contrast, more limited data are available in higher risk, node-positive breast cancer patients, making the exclusion of adjuvant chemotherapy potentially hazardous. 'Prospective-retrospective' studies and limited prospective data show that several signatures, namely Oncotype Dx, MammaPrint, Prosigna, EndoPredict and Breast Cancer Index, select with different levels of success node-positive patients at very low risk for distant recurrence despite not receiving chemotherapy, although the long-term follow-up is still awaited. Pending, however the publication of the results from ongoing randomized studies which enroll patients with node-positive disease, major caution is warranted. Improper use and misinterpretation of these transcriptomic profiles can lead to undertreatment and exposure of patients to unnecessary risks resulting in increased breast cancer mortality for patients with axillary node-positive disease. With this review we critically discuss the available data on gene expression signatures that are used in clinical practice and offer practical recommendations regarding the management of patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive breast cancer.

Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEaRt study.

PURPOSE: HER2-targeted therapies have substantially improved the outcome of patients with breast cancer, however, they can be associated with cardiac toxicity. Guidelines recommend holding HER2-targeted therapies until resolution of cardiac dysfunction. SAFE-HEaRt is the first trial that prospectively tests whether these therapies can be safely administered without interruptions in patients with cardiac dysfunction. METHODS: Patients with stage I-IV HER2-positive breast cancer candidates for trastuzumab, pertuzumab or ado-trastuzumab emtansine (TDM-1), with left ventricular ejection fraction (LVEF) 40-49% and no symptoms of heart failure (HF) were enrolled. All patients underwent cardiology visits, serial echocardiograms and received beta blockers and ACE inhibitors unless contraindicated. The primary endpoint was completion of the planned HER2-targeted therapies without developing either a cardiac event (CE) defined as HF, myocardial infarction, arrhythmia or cardiac death or significant asymptomatic worsening of LVEF. The study was considered successful if planned oncology therapy completion rate was at least 30%. RESULTS: Of 31 enrolled patients, 30 were evaluable. Fifteen patients were treated with trastuzumab, 14 with trastuzumab and pertuzumab, and 2 with TDM-1. Mean LVEF was 45% at baseline and 46% at the end of treatment. Twenty-seven patients (90%) completed the planned HER2-targeted therapies. Two patients experienced a CE and 1 had an asymptomatic worsening of LVEF to ≤ 35%. CONCLUSION: This study provides safety data of HER2-targeted therapies in patients with breast cancer and reduced LVEF while receiving cardioprotective medications and close cardiac monitoring. Our results demonstrate the importance of collaboration between cardiology and oncology providers to allow for delivery of optimal oncologic care to this unique population.

Integrating a newly developed BAC-based physical mapping resource for Lolium perenne with a genome-wide association study across a L. perenne European ecotype collection identifies genomic contexts associated with agriculturally important traits.

BACKGROUND AND AIMS: Lolium perenne (perennial ryegrass) is the most widely cultivated forage and amenity grass species in temperate areas worldwide and there is a need to understand the genetic architectures of key agricultural traits and crop characteristics that deliver wider environmental services. Our aim was to identify genomic regions associated with agriculturally important traits by integrating a bacterial artificial chromosome (BAC)-based physical map with a genome-wide association study (GWAS). METHODS: BAC-based physical maps for L. perenne were constructed from ~212 000 high-information-content fingerprints using Fingerprint Contig and Linear Topology Contig software. BAC clones were associated with both BAC-end sequences and a partial minimum tiling path sequence. A panel of 716 L. perenne diploid genotypes from 90 European accessions was assessed in the field over 2 years, and genotyped using a Lolium Infinium SNP array. The GWAS was carried out using a linear mixed model implemented in TASSEL, and extended genomic regions associated with significant markers were identified through integration with the physical map. KEY RESULTS: Between ~3600 and 7500 physical map contigs were derived, depending on the software and probability thresholds used, and integrated with ~35 k sequenced BAC clones to develop a resource predicted to span the majority of the L. perenne genome. From the GWAS, eight different loci were significantly associated with heading date, plant width, plant biomass and water-soluble carbohydrate accumulation, seven of which could be associated with physical map contigs. This allowed the identification of a number of candidate genes. CONCLUSIONS: Combining the physical mapping resource with the GWAS has allowed us to extend the search for candidate genes across larger regions of the L. perenne genome and identified a number of interesting gene model annotations. These physical maps will aid in validating future sequence-based assemblies of the L. perenne genome.

Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study.

Background: Anti-HER2 therapies are associated with a risk of increased cardiac toxicity, particularly when part of anthracycline-containing regimens. We report cardiac safety of pertuzumab, trastuzumab, and chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. Patients and methods: BERENICE (NCT02132949) is a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (≥10 percentage-points from baseline and to a value of <50%). The main efficacy end point was pathologic complete response (pCR, ypT0/is ypN0). Results are descriptive. Results: Safety populations were 199 and 198 patients in cohorts A and B, respectively. Three patients [1.5%; 95% confidence interval (CI) 0.31% to 4.34%] in cohort A experienced four New York Heart Association class III/IV heart failure events. Thirteen patients (6.5%; 95% CI 3.5% to 10.9%) in cohort A and four (2.0%; 95% CI 0.6% to 5.1%) in cohort B experienced at least one left ventricular ejection fraction decline. No new safety signals were identified. pCR rates were 61.8% and 60.7% in cohorts A and B, respectively. The highest pCR rates were in the HER2-enriched PAM50 subtype (75.0% and 73.7%, respectively). Conclusion: Treatment with pertuzumab, trastuzumab, and common anthracycline-containing regimens for the neoadjuvant treatment of early breast cancer resulted in cardiac and general safety profiles, and pCR rates, consistent with prior studies with pertuzumab. Clinical Trial Information: NCT02132949.

Effect of docetaxel duration on clinical outcomes: exploratory analysis of CLEOPATRA, a phase III randomized controlled trial.

Background: Combination pertuzumab, trastuzumab, and docetaxel (D) is considered standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. This post hoc, exploratory analysis of CLEOPATRA study data evaluated the clinical effects of D treatment duration within this regimen. The clinical benefits of pertuzumab and trastuzumab by different durations of D treatment were also evaluated. Patients and methods: Patients with HER2-positive metastatic breast cancer received trastuzumab and D plus pertuzumab or placebo. Clinical outcomes were analyzed by the number of D cycles that patients received (<6D, 6D, or >6D). Progression-free survival (PFS) and overall survival (OS) for each treatment arm within each D cycle group were estimated using the Kaplan-Meier approach. Time-dependent, multivariate Cox regression was applied to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for HER2-targeted therapy and D cycle groups. Results: Overall, 804 patients received <6D (n = 119), 6D (n = 210), or >6D (n = 475) cycles. After adjusting for pertuzumab benefits versus placebo (PFS HR = 0.61, 95% CI 0.51-0.74, P < 0.0001; OS HR = 0.60, 95% CI, 0.49-0.74, P < 0.0001), >6D versus 6D cycles was not associated with statistically significant improvements in PFS (HR = 0.80, 95% CI 0.63-1.01, P = 0.0640) or OS (HR = 0.88, 95% CI 0.69-1.12, P = 0.3073). Consistent improvements in PFS and OS were observed with pertuzumab versus placebo, irrespective of D duration. The HRs for PFS were 0.395, 0.615, and 0.633 for <6D, 6D, and >6D cycles, respectively (P < 0.05 for all D cycle groups). Corresponding HRs for OS were 0.577, 0.700, and 0.612, respectively (P < 0.05 for <6D and >6D). Conclusions: After accounting for pertuzumab benefits, more than six cycles of D treatment was not associated with significant improvements in either PFS or OS compared with six cycles. The addition of pertuzumab to trastuzumab improved clinical outcomes versus trastuzumab plus placebo, regardless of D treatment duration. ClinicalTrials.gov identifier: NCT00567190.

Incidence and management of diarrhea in patients with HER2-positive breast cancer treated with pertuzumab.

Background: Pertuzumab disrupts heterodimerization between human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), HER3, and HER4. Thus, pertuzumab could result in adverse events similar to those observed with EGFR antagonists, such as diarrhea. We report the incidence and severity of diarrhea observed with pertuzumab in the CLEOPATRA, NeoSphere, and TRYPHAENA studies. Patients and methods: Patients (n = 1443) had metastatic [CLEOPATRA (n = 804)] or early-stage breast cancer [NeoSphere (n = 416) and TRYPHAENA (n = 223)]. The incidence and severity of diarrhea were analyzed by treatment received. The incidence of febrile neutropenia concurrent with diarrhea and the effect of pre-existing gastrointestinal comorbidities were also evaluated. Subgroup analyses were carried out using CLEOPATRA data. Results: The incidence of all-grade diarrhea across studies was generally greater for pertuzumab-based treatment, ranging from 28% to 72% (grade 1, 21%-54%; grade 2, 8%-37%; grade 3, 0%-12%; grade 4, 0%). Incidence was highest during the first pertuzumab-containing cycle, decreasing with subsequent cycles. Dose delays or discontinuations due to diarrhea were infrequent, ranging from 0% to 8%. Among pertuzumab-treated patients with diarrhea, 47%-67% received pharmacological intervention, most commonly with loperamide. Overlap between diarrhea and febrile neutropenia was uncommon, ranging from 0% to 11%. No relationship was observed between pre-existing gastrointestinal comorbidities and diarrhea. In CLEOPATRA, patients ≥65 years treated with pertuzumab had a higher incidence of grade 3 diarrhea than patients <65 years (19% versus 8%). All-grade diarrhea occurred at greater frequency among pertuzumab-treated Asian versus white patients with metastatic breast cancer (74% versus 63%); the corresponding rates in the control arm were 53% and 45%, respectively. Conclusions: In both the metastatic and early-stage breast cancer settings, diarrhea was common but manageable for all pertuzumab-containing regimens. Diarrheal episodes were mainly low grade and occurred most often during the first treatment cycle. Diarrheal-related drug delays or discontinuations were uncommon. ClinicalTrials.gov identifiers: NCT00567190 (CLEOPATRA), NCT00545688 (NeoSphere), NCT00976989 (TRYPHAENA).

Community based kangaroo mother care for low birth weight babies: A pilot study.

BACKGROUND & OBJECTIVES: Kangaroo mother care (KMC - early continuous skin-to-skin contact between mother and infants) has been recommended as an alternative care for low birth weight infants. There is limited evidence in our country on KMC initiated at home. The present study was undertaken to study acceptability of KMC in different community settings. METHODS: A community-based pilot study was carried out at three sites in the States of Odisha, Gujarat and Maharashtra covering rural, urban and rural tribal population, respectively. Trained health workers provided IEC (information, education and communication) on KMC during antenatal period along with essential newborn care messages. These messages were reinforced during the postnatal period. Outcome measures were the proportion of women accepting KMC, duration of KMC/day and total number of days continuing KMC. Focus group discussions and in-depth interviews were also carried out. RESULTS: KMC was provided to 101 infants weighing 1500-2000 g; 57.4 per cent were preterm. Overall, 80.2 per cent mothers received health education on KMC during antenatal period, family members (68.3%) also attended KMC sessions along with pregnant women and 55.4 per cent of the women initiated KMC within 72 h of birth. KMC was provided on an average for five hours per day. Qualitative survey data indicated that the method was acceptable to mothers and family members; living in nuclear family, household work, twin pregnancy, hot weather, etc., were cited as reasons for not being able to practice KMC for a longer duration. INTERPRETATION & CONCLUSIONS: It was feasible to provide KMC using existing infrastructure, and the method was acceptable to most mothers of low birth infants.

Silver doped hydroxyapatite coatings by sacrificial anode deposition under magnetic field.

Uniform distribution of silver (Ag) in the hydroxyapatite (HA) coated Ti surface has been a concern for which an attempt has been made to dope Ag in HA coating with and without magnetic field. Cathodic deposition technique was employed to coat Ag incorporated hydroxyapatite coating using a sacrificial silver anode method by using NdFeB bar magnets producing 12 Tesla magnetic field. While uniform deposition of Ag was observed in the coatings under magnetic field, dense coating was evident in the coating without magnetic field conditions. Uniformly distributed Ag incorporated HA in the present study has potential to fight microorganism while providing osseoconduction properties of the composite coating.

Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study.

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

Does CDKN2A loss predict palbociclib benefit?

Palbociclib, an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6, was recently approved by the U.S. Food and Drug Administration in combination with letrozole for postmenopausal women with advanced hormone receptor-positive, her2-negative breast cancer. Patients with loss of CDKN2A (p16), an inherent negative regulator of cyclin-dependent kinases 4 and 6, were not separately studied because of the significant response of the patients selected based only on receptor status. Here, we report a patient with metastatic estrogen receptor- positive, her2-negative breast cancer with CDKN2A loss who experienced a clinical response to palbociclib.

Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA.

BACKGROUND: Results from the phase III trial CLEOPATRA in human epidermal growth factor receptor 2-positive first-line metastatic breast cancer demonstrated significant improvements in progression-free and overall survival with pertuzumab, trastuzumab, and docetaxel over placebo, trastuzumab, and docetaxel. We carried out exploratory analyses of the incidence and time to development of central nervous system (CNS) metastases in patients from CLEOPATRA. PATIENTS AND METHODS: Patients received pertuzumab/placebo: 840 mg in cycle 1, then 420 mg; trastuzumab: 8 mg/kg in cycle 1, then 6 mg/kg; docetaxel: initiated at 75 mg/m(2). Study drugs were administered i.v. every 3 weeks. The log-rank test was used for between-arm comparisons of time to CNS metastases as first site of disease progression and overall survival in patients with CNS metastases as first site of disease progression. The Kaplan-Meier approach was used to estimate median time to CNS metastases as first site of disease progression and median overall survival. RESULTS: The incidence of CNS metastases as first site of disease progression was similar between arms; placebo arm: 51 of 406 (12.6%), pertuzumab arm: 55 of 402 (13.7%). Median time to development of CNS metastases as first site of disease progression was 11.9 months in the placebo arm and 15.0 months in the pertuzumab arm; hazard ratio (HR) = 0.58, 95% confidence interval (CI) 0.39-0.85, P = 0.0049. Overall survival in patients who developed CNS metastases as first site of disease progression showed a trend in favor of pertuzumab, trastuzumab, and docetaxel; HR = 0.66, 95% CI 0.39-1.11. Median overall survival was 26.3 versus 34.4 months in the placebo and pertuzumab arms, respectively. Treatment comparison of the survival curves was not statistically significant for the log-rank test (P = 0.1139), but significant for the Wilcoxon test (P = 0.0449). CONCLUSIONS: While the incidence of CNS metastases was similar between arms, our results suggest that pertuzumab, trastuzumab, and docetaxel delays the onset of CNS disease compared with placebo, trastuzumab, and docetaxel. CLINICALTRIALSGOV: NCT00567190.

Antimicrobial activity of metal based nanoparticles against microbes associated with diseases in aquaculture.

The emergence of diseases and mortalities in aquaculture and development of antibiotics resistance in aquatic microbes, has renewed a great interest towards alternative methods of prevention and control of diseases. Nanoparticles have enormous potential in controlling human and animal pathogens and have scope of application in aquaculture. The present investigation was carried out to find out suitable nanoparticles having antimicrobial effect against aquatic microbes. Different commercial as well as laboratory synthesized metal and metal oxide nanoparticles were screened for their antimicrobial activities against a wide range of bacterial and fungal agents including certain freshwater cyanobacteria. Among different nanoparticles, synthesized copper oxide (CuO), zinc oxide (ZnO), silver (Ag) and silver doped titanium dioxide (Ag-TiO2) showed broad spectrum antibacterial activity. On the contrary, nanoparticles like Zn and ZnO showed antifungal activity against fungi like Penicillium and Mucor species. Since CuO, ZnO and Ag nanoparticles showed higher antimicrobial activity, they may be explored for aquaculture use.