Showing papers by "Nan Lin published in 2017"

Building a Network Theory of Social Capital

Abstract: This chapter reviews social capital as discussed in the literature, identifies controversies and debates, considers some critical issues, and provides conceptual and research strategies for building a theory. It argues that such a theory and the research enterprise must be based on the fundamental understanding that social capital is captured from embedded resources in social networks. Such measurements can strength of tie network bridge, or intimacy, intensity, interaction and reciprocity be made relative to two frameworks: network resources and contact resources. There are many other measures, such as size, density, cohesion, and closeness of social networks which are candidates as measures for social capital. Network locations are necessary conditions of embedded resources. By considering social capital as assets in networks, the chapter discusses some issues in conceptualization, measurement, and causal mechanism. A proposed model identifies the exogenous factors leading to the acquisition (or the lack) of social capital as well as the expected returns of social capital.

iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics

Abstract: Tumours respond differently to immunotherapies compared with chemotherapeutic drugs, raising questions about the assessment of changes in tumour burden-a mainstay of evaluation of cancer therapeutics that provides key information about objective response and disease progression. A consensus guideline-iRECIST-was developed by the RECIST working group for the use of modified Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to ensure consistent design and data collection, facilitate the ongoing collection of trial data, and ultimate validation of the guideline. This guideline describes a standard approach to solid tumour measurements and definitions for objective change in tumour size for use in trials in which an immunotherapy is used. Additionally, it defines the minimum datapoints required from future trials and those currently in development to facilitate the compilation of a data warehouse to use to later validate iRECIST. An unprecedented number of trials have been done, initiated, or are planned to test new immune modulators for cancer therapy using a variety of modified response criteria. This guideline will allow consistent conduct, interpretation, and analysis of trials of immunotherapies.

Social Capital: Theory and Research

Abstract: Leading scholars in the field of social networks from diverse disciplines present the first systematic and comprehensive collection of current theories and empirical research on the informal connections that individuals have for support, help, and information from other people. Expanding on concepts originally formulated by Pierre Bourdieu and James Coleman, this seminal work will find an essential place with educators and students in the fields of social networks, rational choice theory, institutions, and the socioeconomics of poverty, labor markets, social psychology, and race. The volume is divided into three parts. The first segment clarifies social capital as a concept and explores its theoretical and operational bases. Additional segments provide brief accounts that place the development of social capital in the context of the family of capital theorists, and identify some critical but controversial perspectives and statements regarding social capital in the literature. The editors then make the argument for the network perspective, why and how such a perspective can clarify controversies and advance our understanding of a whole range of instrumental and expressive outcomes. Social Capital further provides a forum for ongoing research programs initiated by social scientists working at the crossroads of formal theory and new methods. These scholars and programs share certain understandings and approaches in their analyses of social capital. They argue that social networks are the foundation of social capital. Social networks simultaneously capture individuals and social structure, thus serving as a vital conceptual link between actions and structural constraints, between micro- and macro-level analyses, and between relational and collective dynamic processes. They are further cognizant of the dual significance of the "structural" features of the social networks and the "resources" embedded in the networks as defining elements of social capital.

Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors

Abstract: Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.

Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study.

Abstract: Background Brain metastases are associated with significant morbidity and mortality. Population-level data describing the incidence and prognosis of patients with brain metastases are lacking. The aim of this study was to characterize the incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy using recently released data from the Surveillance, Epidemiology, and End Results (SEER) program. Methods We identified 1302166 patients with diagnoses of nonhematologic malignancies originating outside of the CNS between 2010 and 2013 and described the incidence proportion and survival of patients with brain metastases. Results We identified 26430 patients with brain metastases at diagnosis of cancer. Patients with small cell and non-small cell lung cancer displayed the highest rates of identified brain metastases at diagnosis; among patients presenting with metastatic disease, patients with melanoma (28.2%), lung adenocarcinoma (26.8%), non-small cell lung cancer not otherwise specified/other lung cancer (25.6%), small cell lung cancer (23.5%), squamous cell carcinoma of the lung (15.9%), bronchioloalveolar carcinoma (15.5%), and renal cancer (10.8%) had an incidence proportion of identified brain metastases of >10%. Patients with brain metastases secondary to prostate cancer, bronchioloalveolar carcinoma, and breast cancer displayed the longest median survival (12.0, 10.0, and 10.0 months, respectively). Conclusions In this study we provide generalizable estimates of the incidence and prognosis for patients with brain metastases at diagnosis of a systemic malignancy. These data may allow for appropriate utilization of brain-directed imaging as screening for subpopulations with cancer and have implications for clinical trial design and counseling of patients regarding prognosis.

Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement

Abstract: Purpose The primary purposes of eligibility criteria are to protect the safety of trial participants and define the trial population. Excessive or overly restrictive eligibility criteria can slow trial accrual, jeopardize the generalizability of results, and limit understanding of the intervention's benefit-risk profile. Methods ASCO, Friends of Cancer Research, and the US Food and Drug Administration examined specific eligibility criteria (ie, brain metastases, minimum age, HIV infection, and organ dysfunction and prior and concurrent malignancies) to determine whether to modify definitions to extend trials to a broader population. Working groups developed consensus recommendations based on review of evidence, consideration of the patient population, and consultation with the research community. Results Patients with treated or clinically stable brain metastases should be routinely included in trials and only excluded if there is compelling rationale. In initial dose-finding trials, pediatric-specific cohorts should be included based on strong scientific rationale for benefit. Later phase trials in diseases that span adult and pediatric populations should include patients older than age 12 years. HIV-infected patients who are healthy and have low risk of AIDS-related outcomes should be included absent specific rationale for exclusion. Renal function criteria should enable liberal creatinine clearance, unless the investigational agent involves renal excretion. Patients with prior or concurrent malignancies should be included, especially when the risk of the malignancy interfering with either safety or efficacy endpoints is very low. Conclusion To maximize generalizability of results, trial enrollment criteria should strive for inclusiveness. Rationale for excluding patients should be clearly articulated and reflect expected toxicities associated with the therapy under investigation.

Brain Metastases in Newly Diagnosed Breast Cancer: A Population-Based Study.

Abstract: Importance Population-based estimates of the incidence and prognosis of brain metastases at diagnosis of breast cancer are lacking. Objective To characterize the incidence proportions and median survivals of patients with breast cancer and brain metastases at the time of cancer diagnosis. Design, Setting, and Participants Patients with breast cancer and brain metastases at the time of diagnosis were identified using the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. Data were stratified by subtype, age, sex, and race. Multivariable logistic and Cox regression were performed to identify predictors of the presence of brain metastases at diagnosis and factors associated with all-cause mortality, respectively. For incidence, we identified a population-based sample of 238 726 adult patients diagnosed as having invasive breast cancer between 2010 and 2013 for whom the presence or absence of brain metastases at diagnosis was known. Patients diagnosed at autopsy or with an unknown follow-up were excluded from the survival analysis, leaving 231 684 patients in this cohort. Main Outcomes and Measures Incidence proportion and median survival of patients with brain metastases and newly diagnosed breast cancer. Results We identified 968 patients with brain metastases at the time of diagnosis of breast cancer, representing 0.41% of the entire cohort and 7.56% of the subset with metastatic disease to any site. A total of 57 were 18 to 40 years old, 423 were 41 to 60 years old, 425 were 61-80 years old, and 63 were older than 80 years. Ten were male and 958 were female. Incidence proportions were highest among patients with hormone receptor (HR)-negative human epidermal growth factor receptor 2 (HER2)-positive (1.1% among entire cohort, 11.5% among patients with metastatic disease to any distant site) and triple-negative (0.7% among entire cohort, 11.4% among patients with metastatic disease to any distant site) subtypes. Median survival among the entire cohort with brain metastases was 10.0 months. Patients with HR-positive HER2-positive subtype displayed the longest median survival (21.0 months); patients with triple-negative subtype had the shortest median survival (6.0 months). Conclusions and Relevance The findings of this study provides population-based estimates of the incidence and prognosis for patients with brain metastases at time of diagnosis of breast cancer. The findings lend support to consideration of screening imaging of the brain for patients with HER2-positive or triple-negative subtypes and extracranial metastases.

The Position Generator: Measurement Techniques for Investigations of Social Capital

Abstract: This chapter argues that the scientific viability of the notion of social capital depends on the development of an approach that integrates theory and measurement of the concept. It illustrates the utility of the position-generator methodology with data from an island-wide survey of employed labor forces in Taiwan. The chapter examines how access to social capital is contingent on a number of structural positions and social contacts, as well as with specific relationships evoking such access. There are two methodologies commonly used to measure access to social capital: name generators and position generators. The position-generator methodology also sheds light on the debate concerning whether the extensity of social contacts or the strength of ties generates better access to social capital. The chapter concludes with the position-generator methodology has yielded consistent findings across a wide spectrum of societies, populations, and political economies.

Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study.

Abstract: PurposeEpigenetic alterations measured in blood may help guide breast cancer treatment. The multisite prospective study TBCRC 005 was conducted to examine the ability of a novel panel of cell-free DNA methylation markers to predict survival outcomes in metastatic breast cancer (MBC) using a new quantitative multiplex assay (cMethDNA).Patients and MethodsTen genes were tested in duplicate serum samples from 141 women at baseline, at week 4, and at first restaging. A cumulative methylation index (CMI) was generated on the basis of six of the 10 genes tested. Methylation cut points were selected to maximize the log-rank statistic, and cross-validation was used to obtain unbiased point estimates. Logistic regression or Cox proportional hazard models were used to test associations between the CMI and progression-free survival (PFS), overall survival (OS), and disease status at first restaging. The added value of the CMI in predicting survival outcomes was evaluated and compared with circulating tumor cells (Ce...

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology–Friends of Cancer Research Brain Metastases Working Group

Abstract: PurposeBroadening trial eligibility to improve accrual and access and to better reflect intended-to-treat populations has been recognized as a priority. Historically, patients with brain metastases have been understudied, because of restrictive eligibility across all phases of clinical trials.MethodsIn 2016, after a literature search and series of teleconferences, a multistakeholder workshop was convened. Our working group focused on developing consensus recommendations regarding the inclusion of patients with brain metastases in clinical trials, as part of a broader effort that encompassed minimum age, HIV status, and organ dysfunction. The working group attempted to balance the needs of protecting patient safety, facilitating access to investigational therapies, and ensuring trial integrity. On the basis of input at the workshop, guidelines were further refined and finalized.ResultsThe working group identified three key populations: those with treated/stable brain metastases, defined as patients who hav...

Abemaciclib for the treatment of brain metastases (BM) secondary to hormone receptor positive (HR+), HER2 negative breast cancer.

Abstract: 1019Background: Abemaciclib is an oral selective CDK4 and CDK6 inhibitor administered on a continuous dosing schedule, which has demonstrated clinical activity and an acceptable safety profile in patients (pts) with heavily pre-treated HR+ metastatic breast cancer (MBC). Abemaciclib has been shown preclinically to cross the blood-brain barrier, providing rationale for testing this agent in pts with BM. Furthermore, as previously presented, levels of abemaciclib similar to plasma were detected in resected BM in a subset of pts with HR+, HER2- MBC in this study. Methods: Study I3Y-MC-JPBO is an open-label, Phase 2, Simon 2-Stage trial evaluating the safety and efficacy of abemaciclib 200 mg BID in pts with new or progressive BM secondary to HR+ MBC, NSCLC, or melanoma. Eligible pts in Part B (the focus of this presentation) include pts with HR+, HER2- MBC who have ≥1 measurable brain lesion. The primary objective was objective intracranial (IC) response rate as defined by Response Assessment in Neuro-Oncolo...

Novel protective role of the circadian nuclear receptor retinoic acid-related orphan receptor-α in diabetic cardiomyopathy

Abstract: Diabetic cardiomyopathy is a major complication that significantly contributes to morbidity and mortality in diabetics with few therapies. Moreover, anti-diabetic drugs reported inconsistent or even adverse cardiovascular effects, suggesting it is important to exploit novel therapeutic targets against diabetic cardiomyopathy. Here, we observed that the nuclear melatonin receptor, the retinoic acid-related orphan receptor α (RORα), was downregulated in diabetic hearts. By utilizing a mouse line with RORα disruption, we demonstrated that RORα deficiency led to significantly augmented diastolic dysfunction and cardiac remodeling induced by diabetes. Microscopic and molecular analyses further indicated that the detrimental effects of RORα deficiency were associated with aggravated myocardial apoptosis, autophagy dysfunction and oxidative stress by disrupting anti-oxidant gene expression. By contrast, restoration of cardiac RORα levels in transgenic mice significantly improved cardiac functional and structural parameters at 8 weeks after diabetes induction. Consistent with genetic manipulation, pharmacological activation of RORα by melatonin and SR1078 (a synthetic agonist) showed beneficial effects against diabetic cardiomyopathy, while the RORα inhibitor SR3335 significantly exacerbated cardiac impairments in diabetic mice. Collectively, these findings suggest that cardiac-targeted manipulation of nuclear melatonin receptor RORα may hold promise for delaying diabetic cardiomyopathy development. This article is protected by copyright. All rights reserved.

Household air pollution and personal exposure to nitrated and oxygenated polycyclic aromatics (PAHs) in rural households: Influence of household cooking energies.

Abstract: Residential solid fuels are widely consumed in rural China, contributing to severe household air pollution for many products of incomplete combustion, such as polycyclic aromatic hydrocarbons (PAHs) and their polar derivatives. In this study, concentrations of nitrated and oxygenated PAH derivatives (nPAHs and oPAHs) for household and personal air were measured and analyzed for influencing factors like smoking and cooking energy type. Concentrations of nPAHs and oPAHs in kitchens were higher than those in living rooms and in outdoor air. Exposure levels measured by personal samplers were lower than levels in indoor air, but higher than outdoor air levels. With increasing molecular weight, individual compounds tended to be more commonly partitioned to particulate matter (PM); moreover, higher molecular weight nPAHs and oPAHs were preferentially found in finer particles, suggesting a potential for increased health risks. Smoking behavior raised the concentrations of nPAHs and oPAHs in personal air significantly. People who cooked food also had higher personal exposures. Cooking and smoking have a significant interaction effect on personal exposure. Concentrations in kitchens and personal exposure to nPAHs and oPAHs for households using wood and peat were significantly higher than for those using electricity and liquid petroleum gas (LPG).

Complete plastome sequencing of both living species of Circaeasteraceae (Ranunculales) reveals unusual rearrangements and the loss of the ndh gene family

Abstract: Among the 13 families of early-diverging eudicots, only Circaeasteraceae (Ranunculales), which consists of the two monotypic genera Circaeaster and Kingdonia, lacks a published complete plastome sequence. In addition, the phylogenetic position of Circaeasteraceae as sister to Lardizabalaceae has only been weakly or moderately supported in previous studies using smaller data sets. Moreover, previous plastome studies have documented a number of novel structural rearrangements among early-divergent eudicots. Hence it is important to sequence plastomes from Circaeasteraceae to better understand plastome evolution in early-diverging eudicots and to further investigate the phylogenetic position of Circaeasteraceae. Using an Illumina HiSeq 2000, complete plastomes were sequenced from both living members of Circaeasteraceae: Circaeaster agrestis and . Plastome structure and gene content were compared between these two plastomes, and with those of other early-diverging eudicot plastomes. Phylogenetic analysis of a 79-gene, 99-taxon data set including exemplars of all families of early-diverging eudicots was conducted to resolve the phylogenetic position of Circaeasteraceae. Both plastomes possess the typical quadripartite structure of land plant plastomes. However, a large ~49 kb inversion and a small ~3.5 kb inversion were found in the large single-copy regions of both plastomes, while Circaeaster possesses a number of other rearrangements, particularly in the Inverted Repeat. In addition, infA was found to be a pseudogene and accD was found to be absent within Circaeaster, whereas all ndh genes, except for ndhE and ndhJ, were found to be either pseudogenized (ΨndhA, ΨndhB, ΨndhD, ΨndhH and ΨndhK) or absent (ndhC, ndhF, ndhI and ndhG) in Kingdonia. Circaeasteraceae was strongly supported as sister to Lardizabalaceae in phylogenetic analyses. The first plastome sequencing of Circaeasteraceae resulted in the discovery of several unusual rearrangements and the loss of ndh genes, and confirms the sister relationship between Circaeasteraceae and Lardizabalaceae. This research provides new insight to characterize plastome structural evolution in early-diverging eudicots and to better understand relationships within Ranunculales .

Left Anterior Temporal Lobe and Bilateral Anterior Cingulate Cortex Are Semantic Hub Regions: Evidence from Behavior-Nodal Degree Mapping in Brain-Damaged Patients.

Abstract: The organizational principles of semantic memory in the human brain are still controversial. Although studies have shown that the semantic system contains hub regions that bind information from different sensorimotoric modalities to form concepts, it is unknown if there are hub regions other than the anterior temporal lobe (ATL). In the meantime, previous studies rarely used network measurements to explore the hubs or correlated network indexes with semantic performance, although the most direct supportive evidence of hubs should come from the network perspective. To fill this gap, we correlated the brain-network index with semantic performance in 86 brain-damaged patients. Specially, we selected the nodal degree measure which reflects how well a node is connected in the network. The measure was calculated as the total number of connections of a given node with other nodes in the resting-state functional MRI network. Semantic ability was measured using the performance of both general and modality-specific (object form, color, motion, sound, manipulation, and function) semantic tasks. We found that the left ATL and the bilateral anterior cingulate cortex (ACC) could be semantic hubs because the reduced nodal degree values of these regions could effectively predict the deficits in both general and modality-specific semantic performance. Moreover, the effects remained when the analyses were performed only in the patients who did not have lesions in these regions. The two hub regions might support semantic representations and executive control processes, respectively. These data provide empirical evidence for the distributed-plus-hub theory of semantic memory from the network perspective. Significance statement Although the distributed-plus-hub organization of semantic memory has been proposed for several years, it remains unclear which hubs other than the anterior temporal lobe are included in the semantic system. Here, we identified such hubs from an innovative network perspective. The voxel-wise nodal degree values were correlated with the performance of general and modality-specific semantic tasks in 86 patients with brain damage. We observed that the left anterior temporal lobe and bilateral anterior cingulate cortex could be semantic hubs because their decreased nodal degree values were significantly correlated with the severity of the deficit in semantic performance. The two hub regions might contribute to semantic representational and control processes, respectively. These offered new evidence for the distributed-plus-hub theory.

TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM).

Abstract: 1005Background: Evidence-based treatments (tx) for metastatic, HER2+ BCBM are limited. We previously found a central nervous system (CNS) objective response rate (ORR) of 8% (95% CI 2-22%) for the irreversible, EGFR/HER2-targeted kinase inhibitor, neratinib. To enhance CNS activity, we evaluated the combination of neratinib + capecitabine in a subsequent cohort, and report results here. Methods: Pts with measurable BCBM (≥ 1 cm in longest dimension) and no prior lapatinib or capecitabine were eligible. All but 3 had CNS progression after local CNS tx. During 21 day cycles, pts received capecitabine 750 mg/m2 twice daily x 14 days followed by 7 days off + neratinib 240 mg orally once daily. Loperamide prophylaxis (16 mg total daily) was recommended during cycle 1. Brain MRI and non-CNS imaging were repeated every 2 cycles until 18 wks, then every 3 cycles. The primary endpoint was composite CNS ORR, requiring all of the following: ≥50% reduction in volumetric sum of target CNS lesions (central review, VORR...

Factors Associated with Early Mortality Among Patients with De Novo Metastatic Breast Cancer: A Population‐Based Study

Abstract: Background Although improvements in survival have been achieved for patients with metastatic breast cancer, some patients experience early death after diagnosis. Patients and methods Using Surveillance, Epidemiology, and End Results data, we identified 26,538 patients with de novo metastatic breast cancer diagnosed between January 1, 2000 and June 30, 2011. We evaluated time trends for deaths at 1 and 6 months after diagnosis. We then restricted the cohort to patients diagnosed between 2010 and 2011 (n = 3,317), when human epidermal growth factor receptor 2 was routinely collected, and examined factors associated with early death. Results In 2000, 15.9% of patients died within 1 month of diagnosis and 33.2% within 6 months. In 2011, the proportion of women dying within 1 month decreased to 13.4% and 26.3% within 6 months (p 8.5 higher odds of dying, and uninsured [versus insured] patients had >2.5 higher odds of death). In addition, in some subgroups (e.g., no insurance and triple negative disease), more than half of patients died within 6 months. Region was also associated with early death. Conclusion Although we observed improvements in the proportion of patients experiencing early death, one quarter of patients with de novo metastatic disease diagnosed in 2011 died within 6 months of diagnosis. In addition to tumor factors and older age, geography and uninsured status were associated with early death. Our findings highlight the need for focused interventions for metastatic patients at highest risk for poor outcomes. The Oncologist 2017;22:386-393 IMPLICATIONS FOR PRACTICE: With nearly one quarter of patients in our dataset diagnosed in 2011 dying within 6 months of diagnosis, our findings highlight the persistent and critical need of further characterization and identification of patients who are risk for poor outcomes in order to optimize care, impact change, and improve outcomes for all women with metastatic breast cancer. Our data also emphasize the need for interventions among those at highest risk for early death. These interventions would likely promote immediate referral for clinical trial participation, early palliative care referrals, and additional supportive services, optimizing equitable patient access to cancer treatment and care.

A Parallel Algorithm for Large-Scale Nonconvex Penalized Quantile Regression

Abstract: Penalized quantile regression (PQR) provides a useful tool for analyzing high-dimensional data with heterogeneity. However, its computation is challenging due to the nonsmoothness and (sometimes) the nonconvexity of the objective function. An iterative coordinate descent algorithm (QICD) was recently proposed to solve PQR with nonconvex penalty. The QICD significantly improves the computational speed but requires a double-loop. In this article, we propose an alternative algorithm based on the alternating direction method of multiplier (ADMM). By writing the PQR into a special ADMM form, we can solve the iterations exactly without using coordinate descent. This results in a new single-loop algorithm, which we refer to as the QPADM algorithm. The QPADM demonstrates favorable performance in both computational speed and statistical accuracy, particularly when the sample size n and/or the number of features p are large. Supplementary material for this article is available online.

Prior Authorization for Medications in a Breast Oncology Practice: Navigation of a Complex Process.

Abstract: Introduction:The cost and burden associated with prior authorization (PA) for specialty medications are concerns for oncologists, but the impact of the PA process on care delivery has not been well described. We examined PA processes and approval patterns within a high-volume breast oncology clinic at a major academic cancer center.Methods:We met with institutional staff to create a PA workflow and process map. We then abstracted pharmacy and medical records for all patients with breast cancer (N = 279) treated at our institution who required a PA between May and November 2015 (324 prescriptions). We examined PA approval rates, time to approval, and associations of these outcomes with the type of medication being prescribed, patient demographics, and method of PA.Results:Seventeen possible process steps and 10 decision points were required for patients to obtain medications requiring a PA. Of the 324 PAs tracked, 316 (97.5%) were approved on the first PA request after an average time of 0.82 days (range, ...

Breast Cancer in the Central Nervous System: Multidisciplinary Considerations and Management.

Abstract: Breast cancer is the second most common primary tumor associated with central nervous system (CNS) metastases Patients with metastatic HER2-positive or triple-negative (estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, HER2-negative) breast cancer are at the highest risk of developing parenchymal brain metastases Leptomeningeal disease is less frequent but is distributed across breast cancer subtypes, including lobular breast cancer Initial treatment strategies can include surgery, radiation, intravenous or intrathecal chemotherapy, and/or targeted approaches In this article, we review the epidemiology of breast cancer brain metastases, differences in clinical behavior and natural history by tumor subtype, and important considerations in the multidisciplinary treatment of these patients We will highlight new findings that impact current standards of care, clinical controversies, and notable investigational approaches in clinical testing

Multiplexed Elimination of Wild-Type DNA and High-Resolution Melting Prior to Targeted Resequencing of Liquid Biopsies.

Abstract: Background: The use of clinical samples and circulating cell-free DNA (cfDNA) collected from liquid biopsies for diagnostic and prognostic applications in cancer is burgeoning, and improved methods that reduce the influence of excess wild-type (WT) portion of the sample are desirable. Here we present enrichment of mutation-containing sequences using enzymatic degradation of WT DNA. Mutation enrichment is combined with high-resolution melting (HRM) performed in multiplexed closed-tube reactions as a rapid, cost-effective screening tool before targeted resequencing. Methods: We developed a homogeneous, closed-tube approach to use a double-stranded DNA-specific nuclease for degradation of WT DNA at multiple targets simultaneously. The No Denaturation Nuclease-assisted Minor Allele Enrichment with Probe Overlap (ND-NaME-PrO) uses WT oligonucleotides overlapping both strands on putative DNA targets. Under conditions of partial denaturation (DNA breathing), the oligonucleotide probes enhance double-stranded DNA-specific nuclease digestion at the selected targets, with high preference toward WT over mutant DNA. To validate ND-NaME-PrO, we used multiplexed HRM, digital PCR, and MiSeq targeted resequencing of mutated genomic DNA and cfDNA. Results: Serial dilution of KRAS mutation-containing DNA shows mutation enrichment by 10- to 120-fold and detection of allelic fractions down to 0.01%. Multiplexed ND-NaME-PrO combined with multiplexed PCR-HRM showed mutation scanning of 10–20 DNA amplicons simultaneously. ND-NaME-PrO applied on cfDNA from clinical samples enables mutation enrichment and HRM scanning over 10 DNA targets. cfDNA mutations were enriched up to approximately 100-fold (average approximately 25-fold) and identified via targeted resequencing. Conclusions: Closed-tube homogeneous ND-NaME-PrO combined with multiplexed HRM is a convenient approach to efficiently enrich for mutations on multiple DNA targets and to enable prescreening before targeted resequencing.

microRNA-199a-5p mediates high glucose-induced reactive oxygen species production and apoptosis in INS-1 pancreatic β-cells by targeting SIRT1.

Abstract: Objective Hyperglycemia-induced pancreatic β-cell loss is a pathologic hallmark of type 2 diabetes mellitus (T2DM). This study was conducted to clarify the function of microRNA (miR)-199a-5p in high glucose-elicited β-cell toxicity and associated molecular mechanisms. Materials and methods INS-1 rat pancreatic β-cells were cultured under normal (11 mM) or high (30 mM) glucose for 16-72 h and examined for miR-199a-5p expression. Gain and loss-of-function studies were performed to determine the role of miR-199a-5p in high glucose-induced apoptosis and reactive oxygen species (ROS) production. Additionally, the involvement of SIRT1 in the action of miR-199a-5p was checked. Results High glucose caused a significant upregulation of miR-199a-5p in INS-1 cells compared to cells under normal glucose conditions. Pre-transfection with anti-miR-199a-5p inhibitors prevented the reduction in cell viability and inhibited ROS generation in INS-1 cells after high glucose treatment. In contrast, overexpression of miR-199a-5p significantly reduced cell viability and promoted apoptosis and ROS formation in INS-1 cells, which was coupled with a downregulation of SIRT1. Knockdown of SIRT1 led to apoptotic death in INS-1 cells. Moreover, enforced expression of SIRT1 blocked miR-199a-5p-induced ROS generation and attenuated high glucose-mediated apoptosis in INS-1 cells. Conclusions miR-199a-5p is upregulated in pancreatic β-cells in response to high glucose and promotes apoptosis and ROS generation by targeting SIRT1. The miR-199a-5p/SIRT1 axis may represent a promising target for the treatment of T2DM.

Choice of ANesthesia for EndoVAScular Treatment of Acute Ischemic Stroke: Protocol for a randomized controlled (CANVAS) trial.

Abstract: BackgroundObservational studies indicate that the type of anesthesia, local or general, may be associated with the post-procedural neurological function in patients with acute ischemic stroke under...

Planned interim analysis of PATRICIA: An open-label, single-arm, phase II study of pertuzumab (P) with high-dose trastuzumab (H) for the treatment of central nervous system (CNS) progression post radiotherapy (RT) in patients (pts) with HER2-positive metastatic breast cancer (MBC).

Abstract: 2074Background: There is currently no clear standard of care to address the management of recurring/multiple intracranial metastases post RT in HER2-positive MBC. The ongoing PATRICIA study (NCT02536339) is evaluating the safety and efficacy of P in combination with high-dose h for patients with HER2-positive MBC with CNS metastases who have CNS progression following RT. Reported herein are results from the protocol-specified interim analysis of PATRICIA. Methods: All eligible patients must have measurable (≥10 mm) CNS progression post RT, and stable non-CNS disease. Patients receive P (840-mg loading dose, then 420 mg every 3 weeks) and high-dose h (6 mg/kg weekly). The primary efficacy endpoint is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. The interim analysis was planned after 15 patients were enrolled and had ≥2 left ventricular ejection fraction (LVEF) measurements, 2 cycles of study drugs, and 2 response measurements. The s...