Effect of pasta in the context of low-glycaemic index dietary patterns on body weight and markers of adiposity: a systematic review and meta-analysis of randomised controlled trials in adults

Objective

Carbohydrate staples such as pasta have been implicated in the obesity epidemic. It is unclear whether pasta contributes to weight gain or like other low-glycaemic index (GI) foods contributes to weight loss. We synthesised the evidence of the effect of pasta on measures of adiposity.

Design

Systematic review and meta-analysis using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

Data sources

MEDLINE, Embase, CINAHL and the Cochrane Library were searched through 7 February 2017.

Eligibility criteria for selecting studies

We included randomised controlled trials ≥3 weeks assessing the effect of pasta alone or in the context of low-GI dietary patterns on measures of global (body weight, body mass index (BMI), body fat) and regional (waist circumference (WC), waist-to-hip ratio (WHR), sagittal abdominal diameter (SAD)) adiposity in adults.

Data extraction and synthesis

Two independent reviewers extracted data and assessed risk of bias. Data were pooled using the generic inverse-variance method and expressed as mean differences (MDs) with 95% CIs. Heterogeneity was assessed (Cochran Q statistic) and quantified (I² statistic). GRADE assessed the certainty of the evidence.

Results

We identified no trial comparisons of the effect of pasta alone and 32 trial comparisons (n=2448 participants) of the effect of pasta in the context of low-GI dietary patterns. Pasta in the context of low-GI dietary patterns significantly reduced body weight (MD=–0.63 kg; 95% CI –0.84 to –0.42 kg) and BMI (MD=–0.26 kg/m²; 95% CI –0.36 to –0.16 kg/m²) compared with higher-GI dietary patterns. There was no effect on other measures of adiposity. The certainty of the evidence was graded as moderate for body weight, BMI, WHR and SAD and low for WC and body fat.

Conclusions

Pasta in the context of low-GI dietary patterns does not adversely affect adiposity and even reduces body weight and BMI compared with higher-GI dietary patterns. Future trials should assess the effect of pasta in the context of other 'healthy' dietary patterns.

Trial registration number

NCT02961088; Results.

https://ift.tt/2q3iAdx

A cross-sectional study of all clinicians conflict of interest disclosures to NHS hospital employers in England 2015-2016

Objective

We set out to document how NHS trusts in the UK record and share disclosures of conflict of interest by their employees.

Design

Cross-sectional study of responses to a Freedom of Information Act request for Gifts and Hospitality Registers.

Setting

NHS Trusts (secondary/tertiary care organisations) in England.

Participants

236 Trusts were contacted, of which 217 responded.

Main outcome measures

We assessed all disclosures for completeness and openness, scoring them for achieving each of five measures of transparency.

Results

185 Trusts (78%) provided a register. 71 Trusts did not respond within the 28 day time limit required by the FoIA. Most COI registers were incomplete by design, and did not contain the information necessary to assess conflicts of interest. 126/185 (68%) did not record the names of recipients. 47/185 (25%) did not record the cash value of the gift or hospitality. Only 31/185 registers (16%) contained the names of recipients, the names of donors, and the cash amounts received. 18/185 (10%) contained none of: recipient name, donor name, and cash amount. Only 15 Trusts had their disclosure register publicly available online (6%). We generated a transparency index assessing whether each Trust met the following criteria: responded on time; provided a register; had a register with fields identifying donor, recipient, and cash amount; provided a register in a format that allowed further analysis; and had their register publicly available online. Mean attainment was 1.9/5; no NHS trust met all five criteria.

Conclusion

Overall, recording of employees' conflicts of interest by NHS trusts is poor. None of the NHS Trusts in England met all transparency criteria. 19 did not respond to our FoIA requests, 51 did not provide a Gifts and Hospitality Register and only 31 of the registers provided contained enough information to assess employees' conflicts of interest. Despite obligations on healthcare professionals to disclose conflicts of interest, and on organisations to record these, the current system for logging and tracking such disclosures is not functioning adequately. We propose a simple national template for reporting conflicts of interest, modelled on the US 'Sunshine Act'.

https://ift.tt/2GtqWGH

Association of dispositional optimism with Lifes Simple 7s Cardiovascular Health Index: results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Sociocultural Ancillary Study (SCAS)

Objectives

Mounting evidence links positive psychological functioning to restorative health processes and favourable medical outcomes. However, very little is known about the relationship between optimism, an indicator of psychological functioning and the American Heart Association (AHA)-defined concept of cardiovascular health (CVH), particularly in Hispanics/Latinos of diverse backgrounds. To address limitations of existing literature, this study investigated the association between dispositional optimism and CVH in a heterogeneous sample of Hispanics/Latinos residing in the USA.

Design

Cross-sectional study.

Participants and setting

Data were analysed from 4919 adults ages 18–75 of the Hispanic Community Health Study/Study of Latinos parent study and the Sociocultural Ancillary Study.

Main outcome measures

Optimism was assessed using the 6-item Life Orientation Test-Revised (range from 6 to 30). AHA classification standards were used to derive an additive CVH score with operationalisation of indicators as Ideal, Intermediate and Poor. The overall CVH score included indicators of diet, body mass index, physical activity, cholesterol, blood pressure, fasting glucose and smoking status. Multivariate linear and logistic regressions were used to examine associations of optimism with CVH (Life's Simple 7), after adjusting for sociodemographic factors and depressive symptoms.

Results

Each increase in the optimism total score was associated with a greater CVH score (β=0.03 per unit increase, 95% CI 0.01 to 0.05). When modelling tertiles of optimism, participants with moderate (β=0.24 to 95% CI 0.06 to 0.42) and high (β=0.12, 95% CI 0.01 to 0.24) levels of optimism displayed greater CVH scores when compared with their least optimistic peers.

Conclusion

This study offers preliminary evidence for an association between optimism and CVH in a large heterogeneous group of Hispanic/Latino adults. Our study adds scientific knowledge of psychological assets that may promote CVH and suggests a novel therapeutic target for consideration. Future studies are needed to explore causality and potential mechanism underlying the relationship between positive emotion and heart health.

https://ift.tt/2q2nA2f

Perceived Quality of In-Service Communication and Counseling Among Adolescents Undergoing Voluntary Medical Male Circumcision

Abstract

Background

Experience with providers shapes the quality of adolescent health services, including voluntary medical male circumcision (VMMC). This study examined the perceived quality of in-service communication and counseling during adolescent VMMC services.

Methods

A postprocedure quantitative survey measuring overall satisfaction, comfort, perceived quality of in-service communication and counseling, and perceived quality of facility-level factors was administered across 14 VMMC sites in South Africa, Tanzania, and Zimbabwe. Participants were adolescent male clients aged 10–14 years (n = 836) and 15–19 years (n = 457) and completed the survey 7 to 10 days following VMMC. Adjusted prevalence ratios (aPRs) were estimated by multivariable modified Poisson regression with generalized estimating equations and robust variance estimation to account for site-level clustering.

Results

Of 10- to 14-year-olds and 15- to 19-year-olds, 97.7% and 98.7%, respectively, reported they were either satisfied or very satisfied with their VMMC counseling experience. Most were also very likely or somewhat likely (93.6% of 10- to 14-year olds and 94.7% of 15- to 19-year olds) to recommend VMMC to their peers. On a 9-point scale, the median perceived quality of in-service (counselor) communication was 9 (interquartile range [IQR], 8–9) among 15- to 19-year-olds and 8 (IQR, 7–9) among 10- to 14-year-olds. The 10- to 14-year-olds were more likely than 15- to 19-year-olds to perceive a lower quality of in-service (counselor) communication (score <7; 21.5% vs. 8.2%; aPR, 1.61 [95% confidence interval, 1.33–1.95]). Most adolescents were more comfortable with a male rather than female counselor and provider. Adolescents of all ages wanted more discussion about pain, wound care, and healing time.

Conclusions

Adolescents perceive the quality of in-service communication as high and recommend VMMC to their peers; however, many adolescents desire more discussion about key topics outlined in World Health Organization guidance.

https://ift.tt/2GtI3nr

Cover

https://ift.tt/2H4WcZx

Scaling Up Voluntary Medical Male Circumcision for Human Immunodeficiency Virus Prevention for Adolescents and Young Adult Men: A Modeling Analysis of Implementation and Impact in Selected Countries

Abstract

Background

The new World Health Organization and Joint United Nations Programme on HIV/AIDS strategic framework for voluntary medical male circumcision (VMMC) aims to increase VMMC coverage among males aged 10–29 years in priority settings to 90% by 2021. We use mathematical modeling to assess the likelihood that selected countries will achieve this objective, given their historical VMMC progress and current implementation options.

Methods

We use the Decision Makers' Program Planning Toolkit, version 2, to examine 4 ambitious but feasible scenarios for scaling up VMMC coverage from 2017 through 2021, inclusive in Lesotho, Malawi, Mozambique, Namibia, South Africa, Swaziland, Tanzania, Uganda, and Zimbabwe.

Results

Tanzania is the only country that would reach the goal of 90% VMMC coverage in 10- to 29-year-olds by the end of 2021 in the scenarios assessed, and this was true in 3 of the scenarios studied. Mozambique, South Africa, and Lesotho would come close to reaching the objective only in the most ambitious scenario examined.

Conclusions

Major changes in VMMC implementation in most countries will be required to increase the proportion of circumcised 10- to 29-year-olds to 90% by the end of 2021. Scaling up VMMC coverage in males aged 10–29 years will require significantly increasing the number of circumcisions provided to 10- to 14-year-olds and 15- to 29-year-olds.

https://ift.tt/2uFIWbl

Impact of Counseling Received by Adolescents Undergoing Voluntary Medical Male Circumcision on Knowledge and Sexual Intentions

Abstract

Background

Little is known regarding the impact of counseling delivered during voluntary medical male circumcision (VMMC) services on adolescents' human immunodeficiency virus (HIV) knowledge, VMMC knowledge, or post-VMMC preventive sexual intentions. This study assessed the effect of counseling on knowledge and intentions.

Methods

Surveys were conducted with 1293 adolescent clients in 3 countries (South Africa, n = 299; Tanzania, n = 498; Zimbabwe, n = 496). Adolescents were assessed on HIV and VMMC knowledge-based items before receiving VMMC preprocedure counseling and at a follow-up survey approximately 10 days postprocedure. Sexually active adolescents were asked about their sexual intentions in the follow-up survey. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated by modified Poisson regression models with generalized estimating equations and robust variance estimators.

Results

Regarding post-VMMC HIV prevention knowledge, older adolescents were significantly more likely than younger adolescents to know that a male should use condoms (age 10–14 years, 41.1%; 15–19 years, 84.2%; aPR, 1.38 [95% CI, 1.19–1.60]), have fewer sex partners (age 10–14 years, 8.1%; age 15–19 years, 24.5%; aPR, 2.10 [95% CI, 1.30–3.39]), and be faithful to one partner (age 10–14 years, 5.7%; age 15–19 years, 23.2%; aPR, 2.79 [95% CI, 1.97–3.97]) to further protect himself from HIV. Older adolescents demonstrated greater improvement in knowledge in most categories, differences that were significant for questions regarding number of sex partners (aPR, 2.01 [95% CI, 1.18–3.44]) and faithfulness to one partner post-VMMC (aPR, 3.28 [95% CI, 2.22–4.86]). However, prevention knowledge levels overall and HIV risk reduction sexual intentions among sexually active adolescents were notably low, especially given that adolescents had been counseled only 7–10 days prior.

Conclusions

Adolescent VMMC counseling needs to be improved to increase knowledge and postprocedure preventive sexual intentions.

https://ift.tt/2H3Tqna

Age Differences in Perceptions of and Motivations for Voluntary Medical Male Circumcision Among Adolescents in South Africa, Tanzania, and Zimbabwe

Abstract

Background

The World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have set a Fast-Track goal to achieve 90% coverage of voluntary medical male circumcision (VMMC) among boys and men aged 10–29 years in priority settings by 2021. We aimed to identify age-specific facilitators of VMMC uptake among adolescents.

Methods

Younger (aged 10–14 years; n = 967) and older (aged 15–19 years; n = 559) male adolescents completed structured interviews about perceptions of and motivations for VMMC before receiving VMMC counseling at 14 service provision sites across South Africa, Tanzania, and Zimbabwe. Adjusted prevalence ratios (aPRs) were estimated using multivariable modified Poisson regression models with generalized estimating equations and robust standard errors.

Results

The majority of adolescents reported a strong desire for VMMC. Compared with older adolescents, younger adolescents were less likely to cite protection against human immunodeficiency virus (HIV) or other sexually transmitted infections (aPR, 0.77; 95% confidence interval [CI], .66–.91) and hygienic reasons (aPR, 0.55; 95% CI, .39–.77) as their motivation to undergo VMMC but were more likely to report being motivated by advice from others (aPR, 1.88; 95% CI, 1.54–2.29). Although most adolescents believed that undergoing VMMC was a normative behavior, younger adolescents were less likely to perceive higher descriptive norms (aPR, 0.79; .71–.89), injunctive norms (aPR, 0.86; 95% CI, .73–1.00), or anticipated stigma for being uncircumcised (aPR, 0.79; 95% CI, .68–.90). Younger adolescents were also less likely than older adolescents to correctly cite that VMMC offers men and boys partial HIV protection (aPR, 0.73; 95% CI, .65–.82). Irrespective of age, adolescents' main concern about undergoing VMMC was pain (aPR, 0.95; 95% CI, .87–1.04). Among younger adolescents, fear of pain was negatively associated with desire for VMMC (aPR, 0.89; 95% CI, .83–.96).

Conclusions

Age-specific strategies are important to consider to generate sustainable demand for VMMC. Programmatic efforts should consider building on the social norms surrounding VMMC and aim to alleviate fears about pain.

https://ift.tt/2uIr9jC

Females’ Peer Influence and Support for Adolescent Males Receiving Voluntary Medical Male Circumcision Services

Abstract

Background

While female involvement in voluntary medical male circumcision (VMMC) has been studied among adults, little is known about the influence of adolescent females on their male counterparts. This study explored adolescent females' involvement in VMMC decision making and the postoperative wound healing process in South Africa, Tanzania, and Zimbabwe.

Methods

Across 3 countries, 12 focus group discussions were conducted with a total of 90 adolescent females (aged 16–19 years). Individual in-depth interviews were conducted 6–10 weeks post-VMMC with 92 adolescent males (aged 10–19 years). Transcribed and translated qualitative data were coded into categories and subcategories by 2 independent coders.

Results

Adolescent female participants reported being supportive of male peers' decisions to seek VMMC, with the caveat that some thought VMMC gives males a chance to be promiscuous. Regardless, females from all countries expressed preference for circumcised over uncircumcised sexual partners. Adolescent females believed VMMC to be beneficial for the sexual health of both partners, viewed males with a circumcised penis as more attractive than uncircumcised males, used their romantic relationships with males or the potential for sex as leveraging points to convince males to become circumcised, and demonstrated supportive attitudes in the wound-healing period. Interviews with males confirmed that encouragement from females was a motivating factor in seeking VMMC.

Conclusions

Adolescent female participants played a role in convincing young males to seek VMMC and remained supportive of the decision postprocedure. Programs aiming to increase uptake of VMMC and other health-related initiatives for adolescent males should consider the perspective and influence of adolescent females.

https://ift.tt/2uD6gWU

Providers’ Perceptions and Training Needs for Counseling Adolescents Undergoing Voluntary Medical Male Circumcision

Abstract

Background

The majority of individuals who seek voluntary medical male circumcision (VMMC) services in sub-Saharan Africa are adolescents (ages 10–19 years). However, adolescents who obtain VMMC services report receiving little information on human immunodeficiency virus (HIV) prevention and care. In this study, we assessed the perceptions of VMMC facility managers and providers about current training content and their perspectives on age-appropriate adolescent counseling.

Methods

Semistructured in-depth interviews were conducted with 33 VMMC providers in Tanzania (n = 12), South Africa (n = 9), and Zimbabwe (n = 12) and with 4 key informant facility managers in each country (total 12). Two coders independently coded the data thematically using a 2-step process and Atlas.ti qualitative coding software.

Results

Providers and facility managers discussed limitations with current VMMC training, noting the need for adolescent-specific guidelines and counseling skills. Providers expressed hesitation in communicating complete sexual health information—including HIV testing, HIV prevention, proper condom usage, the importance of knowing a partner's HIV status, and abstinence from sex or masturbation during wound healing—with younger males (aged <15 years) and/or those assumed to be sexually inexperienced. Many providers revealed that they did not assess adolescent clients' sexual experience and deemed sexual topics to be irrelevant or inappropriate. Providers preferred counseling younger adolescents with their parents or guardians present, typically focusing primarily on wound care and procedural information.

Conclusions

Lack of training for working with adolescents influences the type of information communicated. Preconceptions hinder counseling that supports comprehensive HIV preventive behaviors and complete wound care information, particularly for younger adolescents.

https://ift.tt/2GyxZcP

Title Page

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The Canadian Medical Association and medical marijuana [Letters]

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Patient complaints about Canadian doctors on the rise [News]

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Mobile cell phone technology puts the future of health care in our hands [Commentary]

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Mycobacterium avium complex infection presenting as persistent ascites [Practice]

https://ift.tt/2Io9DTM

Is aldosteronism really a relatively common cause of hypertension? [Letters]

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Cutaneous lymphoid hyperplasia (pseudolymphoma) [Practice]

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Parliament debates junk food ads, vaping [News]

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Vaccinating in the age of apathy: measles vaccination in Canada, 1963-1998 [Humanities]

https://ift.tt/2Efp1zk

Diffuse skin thickening, myalgias and joint stiffness in a 41-year-old man [Correction]

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Cancers, Vol. 10, Pages 103: Role of Gene Therapy in Pancreatic Cancer—A Review

Cancers, Vol. 10, Pages 103: Role of Gene Therapy in Pancreatic Cancer—A Review

Cancers doi: 10.3390/cancers10040103

Authors: Mizuho Sato-Dahlman Keith Wirth Masato Yamamoto

Mortality from pancreatic ductal adenocarcinoma (PDAC) has remained essentially unchanged for decades and its relative contribution to overall cancer death is projected to only increase in the coming years. Current treatment for PDAC includes aggressive chemotherapy and surgical resection in a limited number of patients, with median survival of optimal treatment rather dismal. Recent advances in gene therapies offer novel opportunities for treatment, even in those with locally advanced disease. In this review, we summarize emerging techniques to the design and administration of virotherapy, synthetic vectors, and gene-editing technology. Despite these promising advances, shortcomings continue to exist and here will also be highlighted those approaches to overcoming obstacles in current laboratory and clinical research.

https://ift.tt/2GwWPtN

High-Risk TP53 Mutations Are Associated with Extranodal Extension in Oral Cavity Squamous Cell Carcinoma

Purpose: Development of extranodal extension (ENE) has been associated with poor survival in patients with oral cavity squamous cell carcinoma (OSCC). Here, we sought to confirm the role of ENE as a poor prognostic factor, and identify genomic and epigenetic markers of ENE in order to develop a predictive model and improve treatment selection.

Experimental Design: An institutional cohort (The University of Texas MD Anderson Cancer Center) was utilized to confirm the impact of ENE on clinical outcomes and evaluate the genomic signature of primary and ENE containing tissue. OSCC data from The Cancer Genome Atlas (TCGA) were analyzed for the presence of molecular events associated with nodal and ENE status.

Results: ENE was associated with decreased overall and disease-free survival. Mutation of the TP53 gene was the most common event in ENE⁺ OSCC. The frequency of TP53 mutation in ENE⁺ tumors was higher compared with ENE^– tumors and wild-type (WT) TP53 was highly represented in pN0 tumors. pN⁺ENE⁺ patients had the highest proportion of high-risk TP53 mutations. Both primary tumors (PT) and lymph nodes with ENE (LN) exhibited a high rate of TP53 mutations (58.8% and 58.8%, respectively) with no significant change in allele frequency between the two tissue sites.

Conclusions: ENE is one of the most significant markers of OSCC OS and DFS. There is a shift toward a more aggressive biological phenotype associated with high-risk mutations of the TP53 gene. Prospective clinical trials are required to determine whether TP53 mutational status can be used for personalized treatment decisions. Clin Cancer Res; 24(7); 1727–33. ©2018 AACR.

https://ift.tt/2InDX0K

Personalized Chemosensitivity Assays for Mesothelioma: Are They Worth the Effort?

Cell lines formed from an individual's tumor can be used to predict response to specific therapies and determine genomic predictors. For mesothelioma, where chemotherapy remains the backbone of current therapeutic paradigms, such assays could be used to treat patients with the most effective agents specific to their "chemical profile." Clin Cancer Res; 24(7); 1513–5. ©2018 AACR.

See related article by Schunselaar et al., p. 1761

https://ift.tt/2JclVQk

Survival of Cancer Stem-Like Cells Under Metabolic Stress via CaMK2{alpha}-mediated Upregulation of Sarco/Endoplasmic Reticulum Calcium ATPase Expression

Purpose: Cancer cells grow in an unfavorable metabolic milieu in the tumor microenvironment and are constantly exposed to metabolic stress such as chronic nutrient depletion. Cancer stem-like cells (CSC) are intrinsically resistant to metabolic stress, thereby surviving nutrient insufficiency and driving more malignant tumor progression. In this study, we aimed to demonstrate the potential mechanisms by which CSCs avoid Ca²⁺-dependent apoptosis during glucose deprivation.

Experimental Design: We investigated cell viability and apoptosis under glucose deprivation, performed genome-wide transcriptional profiling of paired CSCs and parental cells, studied the effect of calcium/calmodulin-dependent protein kinase 2 alpha (CaMK2α) gene knockdown, and investigated the role of nuclear factor kappa B (NFB) in CSCs during time-dependent Ca²⁺-mediated and glucose deprivation–induced apoptosis. We also observed the effect of combined treatment with 2-deoxy-d-glucose, a metabolic inhibitor that mimics glucose deprivation conditions in mouse xenograft models, and thapsigargin, a specific inhibitor of sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA).

Results: We demonstrated the coordinated upregulation of SERCA in CSCs. SERCA, in turn, is transcriptionally regulated by CaMK2α via NFB activation. Combined treatment with 2-deoxy-d-glucose and thapsigargin, a specific inhibitor of SERCA, significantly reduced tumor growth compared with that in untreated control animals or those treated with the metabolic inhibitor alone.

Conclusions: The current study provides compelling evidence that CaMK2α acts as a key antiapoptosis regulator in metabolic stress-resistant CSCs by activating NFB. The latter induces expression of SERCA, allowing survival in glucose-deprived conditions. Importantly, our combination therapeutic strategy provides a novel approach for the clinical application of CSC treatment. Clin Cancer Res; 24(7); 1677–90. ©2017 AACR.

https://ift.tt/2Ed2ZNK

Highlights of This Issue

https://ift.tt/2EfIwYs

Establishing a Preclinical Multidisciplinary Board for Brain Tumors

Purpose: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials.

Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC). Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic, and efficacy studies were used to triage active compounds for combination preclinical trials with "standard-of-care" surgery and radiotherapy.

Results: Mouse models displayed distinct patterns of response to surgery, irradiation, and chemotherapy that varied with tumor subtype. Repurposing screens identified 3-hour infusions of gemcitabine as a relatively nontoxic and efficacious treatment of SEP and CPC. Combination neurosurgery, fractionated irradiation, and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP.

Conclusions: We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing. Postirradiation gemcitabine infusion should be tested as new treatments of SEP and CPC. Clin Cancer Res; 24(7); 1654–66. ©2018 AACR.

https://ift.tt/2InDPhM

A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors

Purpose: Preclinical data established IL15 as a homeostatic factor and powerful stimulator of NK and CD8⁺ T-cell function, the basis for clinical testing.

Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday–Friday) subcutaneous injections of rhIL15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL15 and immune biomarkers were evaluated.

Results: Nineteen patients were treated with rhIL15 at dose levels of 0.25, 0.5, 1, 2, and 3 mcg/kg/day. Fourteen patients completed ≥ 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose-limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56^bright subset. A proportional but less dramatic increase was found among circulating CD8⁺ T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients.

Conclusions: SC rhIL15 treatment was well tolerated, producing substantial increases in circulating NK and CD8⁺ T cells. This protocol establishes a safe outpatient SC rhIL15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with potential as a combination immunotherapeutic agent. Clin Cancer Res; 24(7); 1525–35. ©2017 AACR.

https://ift.tt/2JgZo4T

IDH1/2 Mutations Sensitize Acute Myeloid Leukemia to PARP Inhibition and This Is Reversed by IDH1/2-Mutant Inhibitors

Purpose: Somatic mutations in IDH1/2 occur in approximately 20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2^MUT enzymes produce D-2-hydroxyglutarate (D2HG), which associates with increased DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for IDH1/2^MUT AML is not known.

Experimental Design: Well-characterized primary IDH1^MUT, IDH2^MUT, and IDH1/2^WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation, and PARP inhibitors.

Results: IDH1/2^MUT caused increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib in AML cells. IDH1/2^MUT inhibitors protected against these treatments. Combined treatment with a PARP inhibitor and daunorubicin had an additive effect on the killing of IDH1/2^MUT AML cells. We provide evidence that the therapy sensitivity of IDH1/2^MUT cells was caused by D2HG-mediated downregulation of expression of the DNA damage response gene ATM and not by altered redox responses due to metabolic alterations in IDH1/2^MUT cells.

Conclusions: IDH1/2^MUT AML cells are sensitive to PARP inhibitors as monotherapy but especially when combined with a DNA-damaging agent, such as daunorubicin, whereas concomitant administration of IDH1/2^MUT inhibitors during cytotoxic therapy decrease the efficacy of both agents in IDH1/2^MUT AML. These results advocate in favor of clinical trials of PARP inhibitors either or not in combination with daunorubicin in IDH1/2^MUT AML. Clin Cancer Res; 24(7); 1705–15. ©2018 AACR.

https://ift.tt/2InDKL0

First-in-Human Phase I Study of Single-agent Vanucizumab, A First-in-Class Bispecific Anti-Angiopoietin-2/Anti-VEGF-A Antibody, in Adult Patients with Advanced Solid Tumors

Purpose: Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies.

Experimental Design: Patients received escalating biweekly (3–30 mg/kg) or weekly (10–30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control.

Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg biweekly dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related grade ≥3 toxicities. Toxicity was generally higher with weekly than biweekly dosing. A MTD of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6–9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in K^TRANS (measured by dynamic contrast-enhanced MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2,000 mg biweekly dose (phamacokinetically equivalent to 30 mg/kg biweekly) was recommended for further investigation.

Conclusions: Biweekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging antitumor activity in this heterogeneous population. Clin Cancer Res; 24(7); 1536–45. ©2017 AACR.

https://ift.tt/2GO0Bm2

Genomic Correlates of Response to Everolimus in Aggressive Radioiodine-refractory Thyroid Cancer: A Phase II Study

Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine–refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included.

Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis.

Results: Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3–18.5) with a 2-year PFS of 23.6% (95% CI, 10.5–39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8–85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt–mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.

Conclusions: Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine. Clin Cancer Res; 24(7); 1546–53. ©2018 AACR.

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Repurposing Tin Mesoporphyrin as an Immune Checkpoint Inhibitor Shows Therapeutic Efficacy in Preclinical Models of Cancer

Purpose: Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint molecules. This preclinical study investigates heme oxygenase-1 (HO-1), an immunosuppressive enzyme that is expressed in a wide variety of cancers, as a potential immune checkpoint target in the context of a chemotherapy-elicited antitumor immune response. We evaluate repurposing tin mesoporphyrin (SnMP), which has demonstrated safety and efficacy targeting hepatic HO in the clinic for the treatment of hyperbilirubinemia, as an immune checkpoint blockade therapy for the treatment of cancer.

Experimental Design: SnMP and genetic inactivation of myeloid HO-1 were evaluated alongside 5-fluorouracil in an aggressive spontaneous murine model of breast cancer (MMTV-PyMT). Single-cell RNA sequencing analysis, tumor microarray, and clinical survival data from breast cancer patients were used to support the clinical relevance of our observations.

Results: We demonstrate that SnMP inhibits immune suppression of chemotherapy-elicited CD8⁺ T cells by targeting myeloid HO-1 activity in the tumor microenvironment. Microarray and survival data from breast cancer patients reveal that HO-1 is a poor prognostic factor in patients receiving chemotherapy. Single-cell RNA-sequencing analysis suggests that the myeloid lineage is a significant source of HO-1 expression, and is co-expressed with the immune checkpoints PD-L1/2 in human breast tumors. In vivo, we therapeutically compare the efficacy of targeting these two pathways alongside immune-stimulating chemotherapy, and demonstrate that the efficacy of SnMP compares favorably with PD-1 blockade in preclinical models.

Conclusions: SnMP could represent a novel immune checkpoint therapy, which may improve the immunological response to chemotherapy. Clin Cancer Res; 24(7); 1617–28. ©2018 AACR.

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Immune Biomarkers Predictive for Disease-Free Survival with Adjuvant Sunitinib in High-Risk Locoregional Renal Cell Carcinoma: From Randomized Phase III S-TRAC Study

Purpose: Adjuvant sunitinib therapy compared with placebo prolonged disease-free survival (DFS) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov number NCT00375674). A prospectively designed exploratory analysis of tissue biomarkers was conducted to identify predictors of treatment benefit.

Experimental Design: Tissue blocks were used for immunohistochemistry (IHC) staining of programmed cell death ligand 1 (PD-L1), CD4, CD8, and CD68. DFS was compared between < versus ≥ median IHC parameter using the Kaplan–Meier method. For biomarkers with predictive potential, receiver operating characteristics curves were generated.

Results: Baseline characteristics were similar in patients with (n = 191) and without (n = 419) IHC analysis. Among patients with IHC, longer DFS was observed in patients with tumor CD8⁺ T-cell density ≥ versus < median [median (95% CI), not reached (6.83–not reached) versus 3.47 years (1.73–not reached); hazard ratio (HR) 0.40 (95% CI, 0.20–0.81); P = 0.009] treated with sunitinib (n = 101), but not with placebo (n = 90). The sensitivity and specificity for CD8⁺ T-cell density in predicting DFS were 0.604 and 0.658, respectively. Shorter DFS was observed in placebo-treated patients with PD-L1⁺ versus PD-L1^– tumors (HR 1.75; P = 0.103). Among all patients with PD-L1⁺ tumors, DFS was numerically longer with sunitinib versus placebo (HR 0.58; P = 0.175).

Conclusions: Greater CD8⁺ T-cell density in tumor tissue was associated with longer DFS with sunitinib but not placebo, suggesting predictive treatment effect utility. Further independent cohort validation studies are warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk nonmetastatic RCC should also be further explored. Clin Cancer Res; 24(7); 1554–61. ©2018 AACR.

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Extracellular Vesicles Released by Cardiomyocytes in a Doxorubicin-Induced Cardiac Injury Mouse Model Contain Protein Biomarkers of Early Cardiac Injury

Purpose: Cardiac injury is a major cause of death in cancer survivors, and biomarkers for it are detectable only after tissue injury has occurred. Extracellular vesicles (EV) remove toxic biomolecules from tissues and can be detected in the blood. Here, we evaluate the potential of using circulating EVs as early diagnostic markers for long-term cardiac injury.

Experimental Design: Using a mouse model of doxorubicin (DOX)-induced cardiac injury, we quantified serum EVs, analyzed proteomes, measured oxidized protein levels in serum EVs released after DOX treatment, and investigated the alteration of EV content.

Results: Treatment with DOX caused a significant increase in circulating EVs (DOX_EV) compared with saline-treated controls. DOX_EVs exhibited a higher level of 4-hydroxynonenal adducted proteins, a lipid peroxidation product linked to DOX-induced cardiotoxicity. Proteomic profiling of DOX_EVs revealed the distinctive presence of brain/heart, muscle, and liver isoforms of glycogen phosphorylase (GP), and their origins were verified to be heart, skeletal muscle, and liver, respectively. The presence of brain/heart GP (PYGB) in DOX_EVs correlated with a reduction of PYGB in heart, but not brain tissues. Manganese superoxide dismutase (MnSOD) overexpression, as well as pretreatment with cardioprotective agents and MnSOD mimetics, resulted in a reduction of EV-associated PYGB in mice treated with DOX. Kinetic studies indicated that EVs containing PYGB were released prior to the rise of cardiac troponin in the blood after DOX treatment, suggesting that PYGB is an early indicator of cardiac injury.

Conclusions: EVs containing PYGB are an early and sensitive biomarker of cardiac injury. Clin Cancer Res; 24(7); 1644–53. ©2017 AACR.

See related commentary by Zhu and Gius, p. 1516

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Spatially Resolved and Quantitative Analysis of VISTA/PD-1H as a Novel Immunotherapy Target in Human Non-Small Cell Lung Cancer

Purpose: Determine the localized expression pattern and clinical significance of VISTA/PD-1H in human non–small cell lung cancer (NSCLC).

Experimental Design: Using multiplex quantitative immunofluorescence (QIF), we performed localized measurements of VISTA, PD-1, and PD-L1 protein in 758 stage I–IV NSCLCs from 3 independent cohorts represented in tissue microarray format. The targets were selectively measured in cytokeratin⁺ tumor epithelial cells, CD3⁺ T cells, CD4⁺ T-helper cells, CD8⁺ cytotoxic T cells, CD20⁺ B lymphocytes and CD68⁺ tumor-associated macrophages. We determined the association between the targets, clinicopathological/molecular variables and survival. Genomic analyses of lung cancer cases from TCGA were also performed.

Results: VISTA protein was detected in 99% of NSCLCs with a predominant membranous/cytoplasmic staining pattern. Expression in tumor and stromal cells was seen in 21% and 98% of cases, respectively. The levels of VISTA were positively associated with PD-L1, PD-1, CD8⁺ T cells and CD68⁺ macrophages. VISTA expression was higher in T-lymphocytes than in macrophages; and in cytotoxic T cells than in T-helper cells. Elevated VISTA was associated with absence of EGFR mutations and lower mutational burden in lung adenocarcinomas. Presence of VISTA in tumor compartment predicted longer 5-year survival.

Conclusions: VISTA is frequently expressed in human NSCLC and shows association with increased tumor-infiltrating lymphocytes, PD-1 axis markers, specific genomic alterations and outcome. These results support the immunomodulatory role of VISTA in human NSCLC and suggests its potential as therapeutic target. Clin Cancer Res; 24(7); 1562–73. ©2017 AACR.

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Development and Preclinical Validation of a Cysteine Knottin Peptide Targeting Integrin {alpha}v{beta}6 for Near-infrared Fluorescent-guided Surgery in Pancreatic Cancer

Purpose: Intraoperative near-infrared fluorescence (NIRF) imaging could help stratification for the proper primary treatment for patients with pancreatic ductal adenocarcinoma (PDAC), and achieve complete resection, as it allows visualization of cancer in real time. Integrin αvβ6, a target specific for PDAC, is present in >90% of patients, and is able to differentiate between pancreatitis and PDAC. A clinically translatable αvβ6-targeting NIRF agent was developed, based on a previously developed cysteine knottin peptide for PET imaging, R01-MG, and validated in preclinical mouse models.

Experimental Design: The applicability of the agent was tested for cell and tissue binding characteristics using cell-based plate assays, subcutaneous, and orthotopic pancreatic models, and a transgenic mouse model of PDAC development (Pdx1-Cre^tg/+;KRas^{LSL G12D/+};Ink4a/Arf^–/–). IRDye800CW was conjugated to R01-MG in a 1:1 ratio. R01-MG-IRDye800, was compared with a control peptide and IRDye800 alone.

Results: In subcutaneous tumor models, a significantly higher tumor-to-background ratio (TBR) was seen in BxPC-3 tumors (2.5 ± 0.1) compared with MiaPaCa-2 (1.2 ± 0.1; P < 0.001), and to the control peptide (1.6 ± 0.4; P < 0.005). In an orthotopic tumor model, tumor-specific uptake of R01-MG-IRDye800 was shown compared with IRDye800 alone (TBR 2.7 vs. 0.86). The fluorescent signal in tumors of transgenic mice was significantly higher, TBR of 3.6 ± 0.94, compared with the normal pancreas of wild-type controls, TBR of 1.0 ± 0.17 (P < 0.001).

Conclusions: R01-MG-IRDye800 shows specific targeting to αvβ6, and holds promise as a diagnostic and therapeutic tool to recognize PDAC for fluorescence-guided surgery. This agent can help improve the stratification of patients for a potentially curative, margin-negative resection. Clin Cancer Res; 24(7); 1667–76. ©2018 AACR.

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Thy1-Targeted Microbubbles for Ultrasound Molecular Imaging of Pancreatic Ductal Adenocarcinoma

Purpose: To engineer a dual human and murine Thy1-binding single-chain-antibody ligand (Thy1-scFv) for contrast microbubble–enhanced ultrasound molecular imaging of pancreatic ductal adenocarcinoma (PDAC).

Experimental Design: Thy1-scFv were engineered using yeast-surface-display techniques. Binding to soluble human and murine Thy1 and to Thy1-expressing cells was assessed by flow cytometry. Thy1-scFv was then attached to gas-filled microbubbles to create MB_Thy1-scFv. Thy1 binding of MB_Thy1-scFv to Thy1-expressing cells was evaluated under flow shear stress conditions in flow-chamber experiments. MB_{scFv-scrambled} and MB_Non-targeted were used as negative controls. All microbubble types were tested in both orthotopic human PDAC xenografts and transgenic PDAC mice in vivo.

Results: Thy1-scFv had a K_D of 3.4 ± 0.36 nmol/L for human and 9.2 ± 1.7 nmol/L for murine Thy1 and showed binding to both soluble and cellularly expressed Thy1. MB_Thy1-scFv was attached to Thy1 with high affinity compared with negative control microbubbles (P < 0.01) as assessed by flow cytometry. Similarly, flow-chamber studies showed significantly (P < 0.01) higher binding of MB_Thy1-scFv (3.0 ± 0.81 MB/cell) to Thy1-expressing cells than MB_{scFv-scrambled} (0.57 ± 0.53) and MB_Non-targeted (0.43 ± 0.53). In vivo ultrasound molecular imaging using MB_Thy1-scFv demonstrated significantly higher signal (P < 0.01) in both orthotopic (5.32 ± 1.59 a.u.) and transgenic PDAC (5.68 ± 2.5 a.u.) mice compared with chronic pancreatitis (0.84 ± 0.6 a.u.) and normal pancreas (0.67 ± 0.71 a.u.). Ex vivo immunofluorescence confirmed significantly (P < 0.01) increased Thy1 expression in PDAC compared with chronic pancreatitis and normal pancreas tissue.

Conclusions: A dual human and murine Thy1-binding scFv was designed to generate contrast microbubbles to allow PDAC detection with ultrasound. Clin Cancer Res; 24(7); 1574–85. ©2018 AACR.

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Pathways Impacted by Genomic Alterations in Pulmonary Carcinoid Tumors

Purpose: Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, comprise 30% of all carcinoid malignancies, and are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors. The role of specific genomic alterations in the pathogenesis of pulmonary carcinoid tumors remains poorly understood. We sought to identify genomic alterations and pathways that are deregulated in these tumors to find novel therapeutic targets for pulmonary carcinoid tumors.

Experimental Design: We performed integrated genomic analysis of carcinoid tumors comprising whole genome and exome sequencing, mRNA expression profiling and SNP genotyping of specimens from normal lung, TC and AC, and small cell lung carcinoma (SCLC) to fully represent the lung neuroendocrine tumor spectrum.

Results: Analysis of sequencing data found recurrent mutations in cancer genes including ATP1A2, CNNM1, MACF1, RAB38, NF1, RAD51C, TAF1L, EPHB2, POLR3B, and AGFG1. The mutated genes are involved in biological processes including cellular metabolism, cell division cycle, cell death, apoptosis, and immune regulation. The top most significantly mutated genes were TMEM41B, DEFB127, WDYHV1, and TBPL1. Pathway analysis of significantly mutated and cancer driver genes implicated MAPK/ERK and amyloid beta precursor protein (APP) pathways whereas analysis of CNV and gene expression data suggested deregulation of the NF-B and MAPK/ERK pathways. The mutation signature was predominantly C>T and T>C transitions with a minor contribution of T>G transversions.

Conclusions: This study identified mutated genes affecting cancer relevant pathways and biological processes that could provide opportunities for developing targeted therapies for pulmonary carcinoid tumors. Clin Cancer Res; 24(7); 1691–704. ©2018 AACR.

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Development of Anti-Human Mesothelin-Targeted Chimeric Antigen Receptor Messenger RNA–transfected Peripheral Blood Lymphocytes for Ovarian Cancer Therapy

Human Gene Therapy, Ahead of Print.


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In This Issue

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Renin-angiotensin system inhibitors to mitigate cancer treatment-related adverse events

Treatment-related side effects are a major clinical problem in cancer treatment. They lead to reduced compliance to therapy as well as increased morbidity and mortality. Well-known are the sequelae of chemotherapy on the heart, especially in childhood cancer survivors. Therefore, measures to mitigate the adverse events of cancer therapy may improve health and quality of life in cancer patients, both in short and long term. The renin angiotensin system (RAS) affects all hallmarks of cancer, and blockage of the RAS is associated with an improved outcome in several cancer types. There is also increasing evidence that inhibition of the RAS might be able to alleviate or even prevent certain types of cancer treatment related adverse effects. In this review, we summarize the potential of RAS inhibitors to mitigate cancer treatment related adverse events, with a special emphasis on chemotherapy-induced cardiotoxicity, radiation injury, and arterial hypertension.

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CD163 is required for protumoral activation of macrophages in human and murine sarcoma

Recent findings have shown the significance of CD163-positive macrophages in tumor progression, yet there have been few studies on the function of CD163 in macrophages. Here we uncover the role of CD163 in macrophage activation using CD163-deficient mice and human samples. We detected CD163 in 62 undifferentiated pleomorphic sarcoma samples, in which a high percentage of CD163-positive macrophages was associated with decreased overall survival and higher histological grade. We observed macrophage-induced tumor cell proliferation in co-cultures of human monocyte-derived macrophages and leiomyosarcoma (TYLMS-1) and myxofibrosarcoma (NMFH-1) cell lines, which was abrogated by silencing of CD163. Tumor development of sarcoma (MCA205 and LM8) cells in CD163-deficient mice was significantly abrogated in comparison to WT mice. Co-culture with WT peritoneal macrophages significantly increased proliferation of MCA205 cells but decreased in the presence of CD163-deficient macrophages. Production of IL-6 and CXCL2 in CD163-deficient macrophages was suppressed in comparison to WT macrophages, and overexpression of CD163 in CD163-deficient macrophages induced production of IL-6 and CXCL2. Silencing of IL-6 but not CXCL2 abrogated macrophage-induced proliferation of MCA205 cells. Taken together, our results show that CD163 is involved in protumoral activation of macrophages and subsequent development and progression of tumors in mice and humans.

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Network modeling of microRNA-mRNA interactions in neuroblastoma tumorigenesis identifies miR-204 as a direct inhibitor of MYCN

Neuroblastoma is a pediatric cancer of the sympathetic nervous system where MYCN amplification is a key indicator of poor prognosis. However, mechanisms by which MYCN promotes neuroblastoma tumorigenesis are not fully understood. In this study, we analyzed global miRNA and mRNA expression profiles of tissues at different stages of tumorigenesis from TH-MYCN transgenic mice, a model of MYCN-driven neuroblastoma. Based on a Bayesian learning network model in which we compared pre-tumor ganglia from TH-MYCN+/+ mice to age-matched wild-type controls, we devised a predicted miRNA-mRNA interaction network. Among the miRNA-mRNA interactions operating during human neuroblastoma tumorigenesis, we identified miR-204 as a tumor suppressor miRNA that inhibited a subnetwork of oncogenes strongly associated with MYCN-amplified neuroblastoma and poor patient outcome. MYCN bound to the miR-204 promoter and repressed miR-204 transcription. Conversely, miR-204 directly bound MYCN mRNA and repressed MYCN expression. miR-204 overexpression significantly inhibited neuroblastoma cell proliferation in vitro and tumorigenesis in vivo. Together these findings identify novel tumorigenic miRNA gene networks and miR-204 as a tumor suppressor that regulates MYCN expression in neuroblastoma tumorigenesis.

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Contents

Amal Mattu

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Pediatric Pain Management

Nearly 20 years ago, standards were established for hospitals to assess and treat pain in all patients. Research continues to demonstrate evolving trends in the measurement and effective treatment of pain in children. Behavioral research demonstrating long-lasting effects of inadequate pain control during childhood supports the concepts of early and adequate pain control for children suffering from painful conditions in the acute care setting. The authors discuss pain concepts, highlighting factors specific to the emergency department, and include a review of evidence for pharmacologic and nonpharmacologic treatments.

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Emergency Care of Pediatric Burns

Although the overall incidence of and mortality rate associated with burn injury have decreased in recent decades, burns remain a significant source of morbidity and mortality in children. Children with major burns require emergent resuscitation. Resuscitation is similar to that for adults, including pain control, airway management, and administration of intravenous fluid. However, in pediatrics, fluid resuscitation is needed for burns greater than or equal to 15% of total body surface area (TBSA) compared with burns greater than or equal to 20% TBSA for adults. Unique to pediatrics is the additional assessment for non-accidental injury and accurate calculation of the percentage of total burned surface area (TBSA) in children with changing body proportions are crucial to determine resuscitation parameters, prognosis, and disposition.

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Pediatric Minor Head Injury 2.0

Visits for pediatric minor blunt head trauma continue to increase. Variability exists in clinician evaluation and management of this generally low-risk population. Clinical decision rules identify very low-risk children who can forgo neuroimaging. Observation before imaging decreases neuroimaging rates. Outcome data can be used to risk stratify children into more discrete categories. Decision aids improves knowledge and accuracy of risk perception and facilitates identification of caregiver preferences, allowing for shared decision making. For children in whom imaging is performed and is normal or shows isolated linear skull fractures, deterioration and neurosurgical intervention are rare and hospital admission can be avoided.

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Pediatric Emergencies

There are few presentations that strike more fear in the hearts of emergency physicians than the presentation of a sick child. Why is that? Perhaps it is because a child is supposed to be happy and playful, a source of bubbly energy with decades of future productive life and joy, and therefore, there is far more to lose if things go south. Or perhaps it is because devastating illness is so unexpected in children…it is simply not supposed to happen. Or perhaps it is simply because we fear what we do not understand.

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Forthcoming Issues

Hematology Oncology Emergencies

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Copyright

ELSEVIER

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Pediatric Emergency Medicine

EMERGENCY MEDICINE CLINICS OF NORTH AMERICA

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CME Accreditation Page

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In vitro and in vivo activities of DS-2969b, a novel GyrB inhibitor, and its water-soluble prodrug, DS11960558, against methicillin-resistant Staphylococcus aureus [PublishAheadOfPrint]

DS-2969b is a novel GyrB inhibitor under clinical development. In this study, the in vitro activity of DS-2969b and in vivo activities of DS-2969b and its water-soluble prodrug, DS11960558, against methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. DS-2969b inhibited the supercoiling activity of S. aureus DNA gyrase and the decatenation activity of its topoisomerase IV. DS-2969b showed antibacterial activity against Gram-positive aerobes but not against Gram-negative aerobes, except Moraxella catarrhalis and Haemophilus influenzae. DS-2969b was active against MRSA with an MIC₉₀ of 0.25 μg/mL, which was 8-fold lower than that of linezolid. The presence of a pulmonary surfactant did not affect the MIC of DS-2969b. DS-2969b showed time-dependent slow killing against MRSA. The frequency of spontaneous resistance was less than 6.2 x 10^-10 in all four S. aureus isolates at 4x MIC of DS-2969b. In a neutropenic MRSA-induced murine muscle infection model, DS-2969b was more efficacious than linezolid by both subcutaneous and oral routes. DS-2969b and DS11960558 showed efficacy in a neutropenic murine MRSA lung infection model. Pharmacokinetics and pharmacodynamics of DS-2969b and DS11960558 against MRSA were characterized in a neutropenic murine thigh infection model; time above MIC of free drug (f T_MIC) correlated best with in vivo efficacy, and static %f T_MIC was 43—49%. Sufficient f T_MIC was observed in the oral phase 1 multiple-ascending dose study of DS-2969b at 400 mg once a day. These results suggest that DS11960558 and DS-2969b have potential for intravenous-to-oral step-down therapy for treating MRSA infections with higher efficacy than linezolid.

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The Cardiovascular safety of Macrolides: A Systematic review, meta-analysis and network meta-analysis [PublishAheadOfPrint]

Background: Studies reporting an increased risk for cardiac toxicities with macrolide antibiotics have raised concern regarding their cardiovascular safety. We sought to assess the cardiac safety of Macrolide antibiotics as a class and of the individual agents by conducting a systematic review and network meta-analysis.

Methods: MEDLINE, EMBASE and the Cochrane Library were searched up to February 2018, for studies reporting on cardiovascular outcomes with macrolides. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random effects models and odds ratios (OR) and 95% confidence intervals (CI) were calculated for: arrhythmia, cardiovascular death, and myocardial infarction (MI).

Results: A total of 33 studies and 22,601,032 subjects were retrieved and included in the current meta-analyses. Macrolide use was not associated with the risk of arrhythmia or cardiovascular mortality. In the primary analysis macrolide use was associated with a small, but statistically significant 15% increase in risk for MI (OR=1.15 [95%CI 1.02-1.30]). In indirect network meta-analysis, erythromycin and clarithromycin were ranked considerably more likely associated with a higher risk for MI, and significantly associated with increased risk of MI compared to azithromycin (OR=1.58 [95% CI 1.18-2.11] and OR=1.41 [95% CI 1.11-1.81], respectively).

Conclusions: Our findings indicate macrolide antibiotics as a group are associated with a significant risk for MI, but not for arrhythmia and cardiovascular mortality. Among the macrolides, erythromycin and clarithromycin were associated with greater risk of MI. However, it is possible the association between macrolide use and risk of MI is the result of residual confounding.

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The mechanistic basis of pH-dependent 5-flucytosine resistance in Aspergillus fumigatus [PublishAheadOfPrint]

The antifungal drug 5-flucytosine (5FC), a derivative of the nucleobase cytosine, is licenced for treatment of fungal diseases however it is rarely used as a monotherapeutic to treat Aspergillus infection. Despite being potent against other fungal pathogens, 5FC has limited activity against A. fumigatus when standard in vitro assays are used to determine susceptibility. However, in modified in vitro assays where the pH is set to pH 5 the activity of 5FC increases significantly.

Here we provide evidence that fcyB, a gene that encodes a purine-cytosine permease orthologous to known 5FC importers is downregulated at pH 7 and is the primary factor responsible for the low efficacy of 5FC at pH 7. We also uncover two transcriptional regulators that are responsible for repression of fcyB and consequently mediators of 5FC resistance, the CCAAT binding complex (CBC) and the pH regulatory protein PacC. We propose that the activity of 5FC might be enhanced by perturbation of factors that repress fcyB expression such as PacC or other components of the pH sensing machinery.

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Absence of azole or echinocandin resistance in Candida glabrata isolates in India despite background prevalence of strains with defects in DNA mismatch repair pathway [PublishAheadOfPrint]

Candida glabrata infections are increasing world-wide and exhibit greater rates of antifungal resistance than other species. DNA mismatch repair (MMR) gene deletions, such as msh2, in C. glabrata resulting in a mutator phenotype has recently been reported to facilitate rapid acquisition of antifungal resistance. This study determined the antifungal susceptibility profile of 210 C. glabrata isolates, in 10 hospitals in India and investigated the impact of novel MSH2 polymorphisms on mutation potential. No echinocandin or azole resistant strains were detected among C. glabrata isolates and no mutations in FKS hotspot regions supporting our in vitro susceptibility testing results. CLSI antifungal susceptibility data showed MICs of anidulafungin (GM, 0.12μg/ml) and micafungin (GM, 0.01μg/ml) were lower and below the susceptibility breakpoint as compared to that for caspofungin (CAS GM, 1.31μg/ml). Interestingly, 69% of C. glabrata strains sequenced contained six nonsynonymous mutations in MSH2 i.e., V239L, and novel mutations E459K, R847C, Q386K, and T772S. Functional analysis of MSH2 mutations revealed that 49% of tested strains (40/81) contained a partial loss-of-function MSH2 mutation. The novel MSH2 substitution Q386K produced greater frequencies of CAS- resistant colonies upon expression in msh2. However, expression of two other novel MSH2 alleles i.e., E459K or R847C did not confer selection of resistant colonies confirming that not all mutations in MSH2 MMR pathway affects its function or generate a phenotype that is resistant to antifungal drugs. The lack of drug resistance prevented any correlations to be drawn with respect to MSH2 genotype

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EfrEF and the transcription regulator ChlR are required for chlorhexidine stress response in Enterococcus faecalis V583 [PublishAheadOfPrint]

Enterococcus faecalis is an opportunistic pathogen and leading cause of healthcare-associated infections. Daily chlorhexidine gluconate (CHG) bathing of patients is generally regarded as an effective strategy to reduce the occurrence of healthcare-associated infections. It is likely that E. faecalis are frequently exposed to inhibitory and sub-inhibitory CHG in clinical settings. The goal of this study was to investigate how the vancomycin-resistant strain E. faecalis V583 transcriptionally responds to and tolerates stress from CHG. We used transcriptome (microarray) analysis to identify genes up-regulated by E. faecalis V583 in response to CHG. The genes efrE (EF2226) and efrF (EF2227), encoding a heterodimeric ABC transport system, were the most highly up-regulated genes. efrEF expression was induced by CHG at concentrations several two-fold dilutions below the MIC. Deletion of efrEF increased E. faecalis V583 susceptibility to CHG. We found that ChlR, a MerR-like regulator encoded upstream of efrEF, mediated the CHG-dependent up-regulation of efrEF, and deletion of chlR also increased chlorhexidine susceptibility. Overall, our study gives insight into E. faecalis stress responses to a commonly used antiseptic.

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Pharmacokinetics of daptomycin in critically ill pediatric patients [PublishAheadOfPrint]

Daptomycin pharmacokinetics (10 mg/kg once daily) was studied in 4 critically ill pediatric patients aged 8-14 yrs. Area under the curve (AUC_0-) of plasma concentrations on day 1 ranged between 123.8-663.9 μg ⋅ h/ml, with lower values observed in septic and burn patients; clearance ranged between 15.1-80.7 ml/h/kg. Higher than recommended doses of daptomycin may be needed in septic children to ensure optimal drug exposure. Inter-patient variability may suggest a role for therapeutic drug monitoring.

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ST273 carbapenem-resistant Klebsiella pneumoniae carrying blaNDM-1 and blaIMP-4 [PublishAheadOfPrint]

A carbapenem-resistant Klebsiella pneumoniae was recovered from human blood. Its whole genome sequence was obtained using both Illumina and long-read MinION sequencing. The strain belongs to ST273, which has been found recently and caused an outbreak in Southeast Asia. It has two carbapenemase genes bla_NDM-1 (carried by an ST7 IncN self-transmissible plasmid) and bla_IMP-4 (located on an self-transmissible IncHI5 plasmid). Non-KPC-producing ST237 may represent a lineage of carbapenem-resistant K. pneumoniae, which warrants further monitoring.

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Avibactam Pharmacokinetic/Pharmacodynamic Targets [PublishAheadOfPrint]

Avibactam is a novel non-β-lactam β-lactamase inhibitor that has been approved in the USA and Europe for use in combination with ceftazidime. Combinations of avibactam with aztreonam or ceftaroline fosamil have also been clinically evaluated. Until recently, there has been very little precedence of which pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitudes are appropriate to use for β-lactamase inhibitors in population PK modeling for analyzing potential doses and susceptibility breakpoints. For avibactam, several preclinical studies using different in vitro and in vivo models have been conducted to identify the PK/PD index of avibactam and the magnitude of exposure necessary for effect in combination with ceftazidime, aztreonam, or ceftaroline fosamil. The PD driver of avibactam critical for restoring the activity of all three partner β-lactams was found to be time-dependent rather than concentration-dependent, and was defined as the time that the concentration of avibactam exceeded a critical concentration threshold (%fT>C_T). The magnitude of C_T and the time that this threshold needed to be exceeded to elicit particular PD endpoints varied depending on the model and the partner β-lactam. This review describes the preclinical studies used to determine the avibactam PK/PD target in combination with its β-lactam partners.

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Overexpression of the efflux pumps SmeVWX and SmeDEF is a major cause of resistance to cotrimoxazole in Stenotrophomonas maltophilia [PublishAheadOfPrint]

Cotrimoxazole is one of the antimicrobials of choice for treating Stenotrophomonas maltophilia infections. Most works on the molecular epidemiology of resistance to this drugs combination are based in the analysis of sul genes. Nevertheless, the existence of clinical cotrimoxazole resistant S. maltophilia isolates that do not harbor sul genes has been reported. To investigate potential mutations that can reduce the susceptibility of S. maltophilia to cotrimoxazole, spontaneous S. maltophilia cotrimoxazole resistant mutants isolated under different cotrimoxazole concentrations were studied. All mutants presented phenotypes compatible with the overexpression of either SmeVWX (94.6%) or SmeDEF (5.4%). Indeed, the analysis of a selected set of strains showed that overexpression of either one or another of these efflux pumps, which was due to mutations in their regulators smeRv and smeT respectively, was the cause of cotrimoxazole resistance. None other efflux pump was overexpressed in any of the studied mutants, indicating that they do not participate in the observed resistance phenotype. The analysis of mutants overexpressing or lacking SmeDEF or SmeVWX shows that SmeDEF contributes to intrinsic and acquired resistance to cotrimoxazole in S. maltophilia whereas SmeVWX only contributes to acquired resistance. It is important to highlight that all mutants were less susceptible to other antibiotics, including chloramphenicol and quinolones. Since both SmeVWX and SmeDEF are major determinants of quinolone resistance, the potential cross-selection of resistance to cotrimoxazole and quinolones, when either of the antimicrobial is used, is of particular concern for the treatment of S. maltophilia infections.

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Pyocyanin Inhibits Chlamydia Infection by Disabling Infectivity of the Elementary Body and Disrupting Intracellular Growth [PublishAheadOfPrint]

The obligate intracellular bacterium Chlamydia is a widespread human pathogen that causes serious problems including (but not limited to) infertility and blindness. Our search for novel antichlamydial metabolites from marine-derived microorganisms led to isolation of pyocyanin, a small compound from Pseudomonas aeruginosa. Pyocyanin is an effective antichlamydial for all three Chlamydia spp. tested. It has an IC₅₀ of 0.019 ~ 0.028 μM, which is comparable to the IC₅₀ of tetracycline. At concentrations as low as 0.0039 μM, pyocyanin disables infectivity of the chlamydial elementary body (EB). At 0.5 μM or higher concentrations, continuous presence of pyocyanin also inhibits chlamydial growth in the inclusion during later stages of the developmental cycle. Oxidative stress, a major known antimicrobial mechanism of pyocyanin, appears to be responsible for only the inhibition of bacterial growth but not the disinfection of EBs. Pyocyanin is well-tolerated by probiotic vaginal Lactobacillus spp. Our findings suggest that pyocyanin is of therapeutic value for chlamydial infections, and can serve as a valuable chemical probe for studying chlamydial biology.

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SCY-078, a Novel Oral Glucan Synthase Inhibitor, for the Treatment of Invasive Aspergillosis: Evaluation of Antifungal Activity Singly and in Combination [PublishAheadOfPrint]

Invasive aspergillosis remains a major cause of death among the immunocompromised population and those receiving long-term immunosuppressive therapy. In light of increased azole resistance, variable outcomes with existing echinocandin mono and combination therapy, and persistent high mortality rates, new antifungal agents for the treatment of invasive aspergillosis are clearly needed.

SCY-078 is the first in class triterpenoid antifungal, a novel class of glucan synthase inhibitors, with broad in vitro and in vivo activity against a broad spectrum of Candida and Aspergillus. In vitro testing of clinical strains of Aspergillus fumigatus and non-fumigatus strains showed potent fungistatic activity of SCY-078 (minimum effective concentration, MEC₉₀ = 0.125 μg/ml) as compared with amphotericin B (MIC₉₀ = 8 μg/ml) and voriconazole (MIC₉₀ = 2 μg/ml). Combination testing of SCY-078 with isavuconazole or voriconazole demonstrated synergistic activity against the majority of the azole-susceptible strains tested, and SCY-078 in combination with amphotericin B was synergistic against the azole-susceptible strains, as well as one known resistant cyp51A mutant. SCY-078 may be an important additional antifungal for first-line or salvage mono or combination treatment of invasive aspergillosis.

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Tomatidine, a lead antibiotic molecule that targets Staphylococcus aureus ATP synthase subunit C [PublishAheadOfPrint]

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of deadly hospital-acquired infections. The discovery of anti-Staphylococcus antibiotics and new classes of drugs not susceptible to the mechanisms of resistance shared among bacteria is imperative. We recently showed that tomatidine (TO), a steroidal alkaloid from solanaceous plants, possesses potent antibacterial activity against S. aureus small colony variants (SCVs), the notoriously persistent form of this bacterium that has been associated with recurrence of infections. Here, using genomic analysis of in vitro-generated TO-resistant S. aureus strains to identify mutations in genes involved in resistance, we identified the bacterial ATP synthase as the cellular target. Sequence alignments were performed to highlight the modified sequences and the structural consequences of the mutations were evaluated in structural models. Overexpression of the atpE gene in S. aureus SCVs or introducing the mutation found in the atpE gene of one of the high-level TO-resistant S. aureus mutant into the Bacillus subtilis atpE gene provided resistance to TO and further validated the identity of the cellular target. FC04-100, a TO derivative which also possesses activity against non-SCV strains, prevents high-level resistance development in prototypic strains and limits the level of resistance observed in SCVs. An ATP synthesis assay allowed the observation of a correlation between antibiotic potency and ATP synthase inhibition. The selectivity index (inhibition of ATP production by mitochondria vs. bacterial ATP synthase) is estimated to be >10⁵-fold for FC04-100.

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Relebactam is a Potent Inhibitor of the KPC-2 {beta}-Lactamase and Restores the Susceptibility of Imipenem Against KPC-Producing Enterobacteriaceae [PublishAheadOfPrint]

The imipenem-relebactam combination is in development as a potential treatment regimen for infections caused by Enterobacteriaceae possessing complex β-lactamase backgrounds. Relebactam is a β-lactamase inhibitor that possesses the diazabicyclooctane core similar to avibactam, however relebactam's R1 side chain also includes a piperidine ring compared to the carboxyamide of avibactam. Here, we investigated the inactivation of Klebsiella pneumoniae carbapenemase (KPC-2), the most widespread class A carbapenemase, by relebactam and performed susceptibility testing with imipenem-relebactam using KPC-producing clinical isolates of Enterobacteriaceae. Minimal inhibitory concentration (MIC) measurements using agar dilution methods revealed that all 101 clinical isolates of KPC-producing Enterobacteriaceae (K. pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Enterobacter aerogenes, Citrobacter freundii, Citrobacter koseri, and Escherichia coli) were highly susceptible to imipenem-relebactam (MICs ≤ 2 mg/L). Relebactam inhibited KPC-2 with a k₂/K value of 24,750 M^-1s^-1 and demonstrated a slow k_off of 0.0002 s^-1. Biochemical analysis using time-based mass spectrometry to map intermediates revealed that the KPC-2-relebactam acyl-enzyme complex was stable for up to 24 hours. Importantly, desulfation of relebactam was not observed using mass spectrometry. Desulfation and subsequent deacylation has been observed during the reaction of KPC-2 with avibactam. Upon molecular dynamics simulations of relebactam in the KPC-2 active site, we found that in comparison to the KPC-2-avibactam, the positioning of active site water molecules is less favorable for desulfation. In the acyl-complexes, the water molecules are within 2.5-3 Å of the avibactam sulfate, however more than 5-6 Å from the relebactam sulfate. As a result, we propose that the KPC-2-relebactam acyl-complex is more stable than the KPC-2-avibactam acyl-enzyme complex. The clinical implications of this difference are not currently known.

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Fungicidal potency and mechanisms of {theta}-defensins against multi-drug resistant Candida species [PublishAheadOfPrint]

Systemic candidiasis is a growing health care concern becoming even more challenging due to the growing frequency of infections caused by multidrug resistant (MDR) Candida spp. Thus there is an urgent need for new therapeutic approaches to candidiasis, including strategies bioinspired by insights into natural host defense against fungal pathogens. The antifungal properties of -defensins, macrocyclic peptides expressed in tissues of Old World monkeys, were investigated against a panel of drug sensitive and drug resistant clinical isolates of C. albicans and non-albicans Candida spp. Rhesus -defensin 1 (RTD-1), the prototype -defensin, was rapidly and potently fungicidal against drug sensitive and MDR C. albicans strains. Fungal killing occurred by cell permeabilization that was temporally correlated with ATP release and intracellular accumulation of reactive oxygen species (ROS). Killing by RTD-1 was compared with that of histatin 5 (Hst 5), an extensively characterized anticandidal peptide expressed in human saliva. RTD-1 killed C. albicans much more rapidly and at >200-fold lower concentration than Hst 5. Unlike Hst 5, the anticandidal activity of RTD-1 was independent of mitochondrial ATP production. Moreover, RTD-1 was completely resistant to Candida proteases for 2 h under conditions that rapidly and completely degraded Hst 5. Minimal inhibitory and fungicidal concentrations (MIC/MFC) of 14 natural -defensins isoforms against drug resistant C. albicans isolates identified peptides that are more active than amphotericin B and/or caspofungin against fluconazole resistant organisms, including MDR C. auris. These results point to the potential of macrocyclic -defensins as structural templates for design of antifungal therapeutics.

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The Combination of Daptomycin plus Fosfomycin has Synergistic, Potent and Rapid Bactericidal Activity against Methicillin-Resistant Staphylococcus aureus (MRSA) in a Rabbit Model of Experimental Endocarditis (EE). [PublishAheadOfPrint]

This study aims to investigate whether the addition of fosfomycin or cloxacillin to daptomycin provides better outcomes in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) experimental aortic endocarditis in rabbits. Five MRSA strains were used to perform in vitro time-kill studies at standard (105) and high (108) inocula. Combined therapy was compared with daptomycin monotherapy treatment in the MRSA experimental endocarditis model. A human-like pharmacokinetics model was applied and the equivalents of cloxacillin 2g/4hiv, fosfomycin 2g/6h iv and daptomycin 6-10mg/kg/d iv were administered. The combination of daptomycin and fosfomycin or cloxacillin was synergistic in the five strains tested at both inocula. A bactericidal effect was detected in four out of five strains tested with both combinations. The MRSA-277 strain (vancomycin MIC, 2 mcg/mL) was used for the experimental endocarditis model. Daptomycin plus fosfomycin significantly improved the efficacy of daptomycin monotherapy at 6 mg/kg/d in terms of both the proportion of sterile vegetations (100% vs. 72%, P=.046) and the decrease in the density of bacteria within the vegetations (P=.025). Daptomycin plus fosfomycin was as effective as daptomycin monotherapy at 10 mg/kg/d (100% vs. 93%, P=1.00) and had similar activity to daptomycin plus cloxacillin when daptomycin was administered at 6 mg/kg/d (100% vs. 88%, P=0.48). Daptomycin non-susceptibility was not detected in any of the isolates recovered from vegetations. In conclusion, for the treatment of MRSA experimental endocarditis, the combination of daptomycin plus fosfomycin showed synergistic and bactericidal activity.

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Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers [Research Briefs]

NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMAs) of the lung. The oncoprotein binds ERBB3-ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 monoclonal antibody therapy (GSK2849330) in an exceptional responder with an NRG1-rearranged IMA on a phase 1 trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four NRG1-rearranged IMA patients (including the index patient post-GSK2849330). While in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound anti-tumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and endometrial cancers.

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Antibiotics, Acid-Suppressive Meds Tied to Allergic Disease

MONDAY, April 2, 2018 -- The use of acid-suppressive medications and antibiotics during the first six months of infancy is tied to subsequent development of allergic disease, according to a study published online April 2 in JAMA Pediatrics. Edward...

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Zika Vaccine Could Essentially Eliminate Prenatal Infection

MONDAY, April 2, 2018 -- A Zika vaccine could substantially prevent future outbreaks through a combination of direct protection and indirect transmission reduction, according to a modeling study published online April 3 in the Annals of Internal...

https://ift.tt/2Gy2Bev

apoE Aggregation May Impact apoE-Mediated Plaque Formation

MONDAY, April 2, 2018 -- A primary mechanism for APOE gene (apoE)-mediated plaque formation may result from apoE aggregation, according to a study published online March 30 in the Journal of Clinical Investigation. Fan Liao, Ph.D., from the...

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Agile Implementation Speeds Initiation of Health Care Solutions

MONDAY, April 2, 2018 -- In a case demonstration study published online March 7 in the Journal of the American Geriatrics Society, authors describe using Agile Implementation (AI), a method to quickly, efficiently, effectively, and sustainably...

https://ift.tt/2uMzDpM

Obstetrician-Gynecologists Can Help Protect Working Mothers

MONDAY, April 2, 2018 -- Obstetrician-gynecologists and other obstetric providers can help to protect women working through their pregnancy, according to a Committee Opinion published in the April issue of Obstetrics & Gynecology. Rebecca...

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Testing for HbA1c, in addition to the oral glucose tolerance test, in screening for abnormal glucose regulation helps to reveal patients with early β-cell function impairment

Authors: Li, Yu-Hsuan / Sheu, Wayne Huey-Herng / Lee, Wen-Jane / Lee, I-Te / Lin, Shih-Yi / Lee, Wen-Lieng / Liang, Kae-Woei / Wang, Jun-Sing


https://ift.tt/2J2JsDe

Harmonization initiatives in the generation, reporting and application of biological variation data

Authors: Aarsand, Aasne K. / Røraas, Thomas / Bartlett, William A. / Coşkun, Abdurrahman / Carobene, Anna / Fernandez-Calle, Pilar / Jonker, Niels / Díaz-Garzón, Jorge / Braga, Federica / Sandberg, Sverre /


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Frontmatter

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S16-2. Strategy in anesthetic management for intraoperative neuromonitoring

The development of postoperative functional dysfunction can have an impact on the length of hospital stay, total medical costs, and necessity of dependency. To maintain functional integrity, neuromonitoring including motor evoked potential (MEP), sensory evoked potential, and visual evoked potential, has been conducted during the operation. Anesthetic management is usually based on the maintenance of MEP, which is most susceptible to suppression by anesthetic agents. MEP is indicated for craniotomy, spine surgery and aortic surgery, in which the technique for stimulation and recording can vary on types of surgery.

https://ift.tt/2GOkv0c

Pasta De Lassar Andromaco Skin Protectant 25 Percent Zinc Oxide by MarcasUSA: Recall - Potential Contamination

Audience: Consumer, Pediatrics [Posted 04/02/2018] ISSUE: MarcasUSA, LLC and Industria Farmacéutica Andromaco, S.A. de C.V. voluntarily recalled four lots of Pasta De Lassar Andromaco Skin Protectant, 25% zinc oxide to the retail level. FDA...

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Potential of quantitative SEPT9 and SHOX2 methylation in plasmatic circulating cell-free DNA as auxiliary staging parameter in colorectal cancer: a prospective observational cohort study

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Money-Back Guarantees for Expensive Drugs: Wolf's Clothing but a Sheep Underneath

In this issue, Kazi and colleagues show that a money-back guarantee for the lipid-lowering drug evolocumab will improve the drug's net cost-effectiveness by approximately 3% at most. The editorialists discuss why such guarantees for expensive drugs are more marketing legerdemain than an effective way to moderate drug costs.

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Effect of Money-Back Guarantees on the Cost-Effectiveness of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors

https://ift.tt/2GugTRu

Evaluating Vaccination Strategies for Zika Virus in the Americas

Background:

Mosquito-borne and sexually transmitted Zika virus has become widespread across Central and South America and the Caribbean. Many Zika vaccine candidates are under active development.

Objective:

To quantify the effect of Zika vaccine prioritization of females aged 9 to 49 years, followed by males aged 9 to 49 years, on incidence of prenatal Zika infections.

Design:

A compartmental model of Zika transmission between mosquitoes and humans was developed and calibrated to empirical estimates of country-specific mosquito density. Mosquitoes were stratified into susceptible, exposed, and infected groups; humans were stratified into susceptible, exposed, infected, recovered, and vaccinated groups. Age-specific fertility rates, Zika sexual transmission, and country-specific demographics were incorporated.

Setting:

34 countries and territories in the Americas with documented Zika outbreaks.

Target Population:

Males and females aged 9 to 49 years.

Intervention:

Age- and sex-targeted immunization using a Zika vaccine with 75% efficacy.

Measurements:

Annual prenatal Zika infections.

Results:

For a base-case vaccine efficacy of 75% and vaccination coverage of 90%, immunizing females aged 9 to 49 years (the World Health Organization target population) would reduce the incidence of prenatal infections by at least 94%, depending on the country-specific Zika attack rate. In regions where an outbreak is not expected for at least 10 years, vaccination of women aged 15 to 29 years is more efficient than that of women aged 30 years or older.

Limitation:

Population-level modeling may not capture all local and neighborhood-level heterogeneity in mosquito abundance or Zika incidence.

Conclusion:

A Zika vaccine of moderate to high efficacy may virtually eliminate prenatal infections through a combination of direct protection and transmission reduction. Efficiency of age-specific targeting of Zika vaccination depends on the timing of future outbreaks.

Primary Funding Source:

National Institutes of Health.

https://ift.tt/2q0Dryf

Pasta De Lassar Andromaco Skin Protectant 25 Percent Zinc Oxide by MarcasUSA: Recall - Potential Contamination

Audience: Consumer, Pediatrics [Posted 04/02/2018] ISSUE: MarcasUSA, LLC and Industria Farmacéutica Andromaco, S.A. de C.V. voluntarily recalled four lots of Pasta De Lassar Andromaco Skin Protectant, 25% zinc oxide to the retail level. FDA...

https://ift.tt/2EeNFQv

Annals Story Slam - Escape From Iraq: A Refugee Family's Story of Resilience and Hope

https://ift.tt/2EchGQZ

Literacy-Adapted Cognitive Behavioral Therapy Versus Education for Chronic Pain at Low-Income Clinics A Randomized Controlled Trial

Background:

Chronic pain is common and challenging to treat. Although cognitive behavioral therapy (CBT) is efficacious, its benefit in disadvantaged populations is largely unknown.

Objective:

To evaluate the efficacy of literacy-adapted and simplified group CBT versus group pain education (EDU) versus usual care.

Design:

Randomized controlled trial. (ClinicalTrials.gov: NCT01967342)

Setting:

Community health centers serving low-income patients in Alabama.

Patients:

Adults (aged 19 to 71 years) with mixed chronic pain.

Interventions:

CBT and EDU delivered in 10 weekly 90-minute group sessions.

Measurements:

Self-reported, postintervention pain intensity (primary outcome) and physical function and depression (secondary outcomes).

Results:

290 participants were enrolled (70.7% of whom were women, 66.9% minority group members, 72.4% at or below the poverty level, and 35.8% reading below the fifth grade level); 241 (83.1%) participated in posttreatment assessments. Linear mixed models included all randomly assigned participants. Members of the CBT and EDU groups had larger decreases in pain intensity scores between baseline and posttreatment than participants receiving usual care (estimated differences in change scores—CBT: −0.80 [95% CI −1.48 to −0.11]; P = 0.022; EDU: −0.57 [CI, −1.04 to −0.10]; P = 0.018). At 6-month follow-up, treatment gains were not maintained in the CBT group but were still present in the EDU group. With regard to physical function, participants in the CBT and EDU interventions had greater posttreatment improvement than those receiving usual care, and this progress was maintained at 6-month follow-up. Changes in depression (secondary outcome) did not differ between either the CBT or EDU group and the usual care group.

Limitations:

Participants represented a single health care system. Self-selection bias may have been present.

Conclusion:

Simplified group CBT and EDU interventions delivered at low-income clinics significantly improved pain and physical function compared with usual care.

Primary Funding Source:

Patient-Centered Outcomes Research Institute.

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A Call for Open-Source Cost-Effectiveness Analysis

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Colonoscopy and Colorectal Cancer Mortality in the Veterans Affairs Health Care System A Case–Control Study

Background:

Colonoscopy is widely used in the Veterans Affairs (VA) health care system for colorectal cancer (CRC) prevention, but its effect on CRC mortality is unknown.

Objective:

To determine whether colonoscopy is associated with decreased CRC mortality in veterans and whether its effect differs by anatomical location of CRC.

Design:

Case–control study.

Setting:

VA–Medicare administrative data.

Participants:

Case patients were veterans aged 52 years or older who were diagnosed with CRC between 2002 and 2008 and died of the disease by the end of 2010. Case patients were matched to 4 control patients without prior CRC on the basis of age, sex, and facility. Conditional logistic regression was performed to calculate odds ratios (ORs) for exposure to colonoscopy, with adjustment for race, Charlson Comorbidity Index score, selected chronic conditions, nonsteroidal anti-inflammatory drug use, and family history of CRC.

Measurements:

Exposure to colonoscopy was determined from 1997 to 6 months before CRC diagnosis in case patients and to a corresponding date in control patients. Subgroup analysis was performed for patients who had undergone screening colonoscopy.

Results:

A total of 4964 case patients and 19 856 control patients were identified. Case patients were significantly less likely to have undergone any colonoscopy (OR, 0.39 [95% CI, 0.35 to 0.43]). Colonoscopy was associated with reduced mortality for left-sided cancer (OR, 0.28 [CI, 0.24 to 0.32]) and right-sided cancer (OR, 0.54 [CI, 0.47 to 0.63]). The results were similar for patients who had undergone screening colonoscopy (overall OR, 0.30 [CI, 0.24 to 0.38]). Sensitivity analyses that varied the interval between CRC diagnosis and colonoscopy exposure did not affect the primary findings.

Limitation:

Unmeasured confounding.

Conclusion:

In this study using national VA–Medicare data, colonoscopy was associated with significant reductions in CRC mortality among veterans and was associated with greater benefit for left-sided cancer than right-sided cancer.

Primary Funding Source:

U.S. Department of Veterans Affairs.

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On Seeing Your Obituary in the Newspaper

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Should This Patient Receive Prophylactic Medication to Prevent Delirium? Grand Rounds Discussion From Beth Israel Deaconess Medical Center

In 2015, the American Geriatrics Society released recommendations for prevention and management of postoperative delirium, based on a systematic literature review and evaluation of nonpharmacologic and pharmacologic approaches by an expert panel. The guidelines recommend an interdisciplinary focus on nonpharmacologic measures (reorientation, medication management, early mobility, nutrition, and gastointestinal motility) for prevention and consideration of this strategy for acute management. They also recommend optimizing nonopioid medication as a means to manage pain and avoiding benzodiazepines other than to treat substance withdrawal. The authors concluded that evidence to recommend antipsychotics for prevention of delirium is insufficient but that these drugs may be considered for short-term treatment in the setting of imminent harm to the patient or caregivers or severe distress due to agitation. Patients should be given the lowest possible dose for the shortest duration when other nonpharmacologic measures have failed. In this Beyond the Guidelines, a psychiatrist and a geriatrician debate whether Mr. W, a 79-year-old man at high risk for postoperative delirium, should receive prophylactic antipsychotics with his next surgery. They review risk factors, appropriate evaluation, and potential benefits and harms of the various medications often used in this setting.

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Annals Story Slam - To Save One Life Is to Save the World

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Hidden Curricula, Ethics, and Professionalism: Optimizing Clinical Learning Environments in Becoming and Being a Physician: A Position Paper of the American College of Physicians

Much of what is formally taught in medicine is about the knowledge, skills, and behaviors required of a physician, including how to express compassion and respect for patients at the bedside. What is learned, however, includes not only admirable qualities but also behaviors and qualities that are inconsistent with ethics and professionalism. Positive role models may reinforce the character and values the profession seeks to cultivate; negative ones directly contradict classroom lessons and expectations of patients, society, and medical educators. These positive and negative lessons, which are embedded in organizational structure and culture, are the hidden curricula conveyed in medical schools, residency programs, hospitals, and clinics. This position paper from the American College of Physicians focuses on ethics, professionalism, and the hidden curriculum. It provides strategies for revealing what is hidden to foster the development of reflective and resilient lifelong learners who embody professionalism and clinicians who are, and are perceived as, positive role models. Making the hidden visible and the implicit explicit helps to create a culture reflecting medicine's core values.

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Continuous Glucose Monitoring in Patients With Type 2 Diabetes Receiving Insulin Injections

https://ift.tt/2InWnOU

Time for Value-Based Payment Models to Adopt a Disparities-Sensitive Frame Shift

Evidence suggests that the current growth in value-based payment models may unintentionally worsen health care disparities by disadvantaging hospitals caring for socially at-risk populations. To address this tension, value-based payment models should adopt a disparities-sensitive frame shift to integrate measures of equity into hospitals' financial calculus, incentivizing hospitals to tackle the disparities challenge without losing sight of quality.

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Correction: Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older to Higher Versus Lower Blood Pressure Targets

https://ift.tt/2Ef0iuU

The CVS–Aetna Merger: Another Large Bet on the Changing U.S. Health Care Landscape

Through mergers and acquisitions, health care organizations are making large bets about the future of the U.S. medical landscape and the types of organizations that can ultimately succeed in it. There's been a recent uptick in vertical integration, such as hospitals buying physician practices and insurers buying providers. This commentary discusses the recently announced merger of CVS and Aetna and whether it will benefit consumers.

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Psoriasis

Psoriasis, an inherited disorder of the immune system, presents most commonly in the skin and joints but is also associated with cardiovascular, metabolic, and neuropsychiatric effects. Treatments include topical therapy for mild disease; phototherapy and oral therapy, such as retinoids and immunomodulating agents; and targeted biologic therapies that have revolutionized treatment of psoriasis and psoriatic arthritis. Primary care physicians should be aware of the systemic associations of psoriasis and the treatments available for this disorder.

https://ift.tt/2InPP2Y

Seven Deadly Sins Resulting From the Centers for Disease Control and Prevention's Seven Forbidden Words

Recently, it was reported that Centers for Disease Control and Prevention (CDC) staff were advised to avoid using the following 7 words in budget documents: "vulnerable," "entitlement," "diversity," "transgender," "fetus," "evidence-based," and "science-based." This commentary discusses the implications of such censorship on the work and credibility of the CDC and other U.S. government health organizations.

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Annals Story Slam - Lessons From Crying

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Cautions as Regulators Move to End Exclusive Reliance on Intention to Treat

Intention-to-treat (ITT) analyses of randomized trials have been favored because they alleviate concerns about baseline confounding, but ITT analyses estimate the effect of being assigned to an intervention rather than that of actually receiving it. Regulators, pharmaceutical companies, and academics are advocating approaches to complement ITT analyses. This commentary presents specifications to consider for such approaches.

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Hot Tea Consumption and the Risk for Esophageal Cancer

https://ift.tt/2E5K34n

Frequency of Poison Center Exposures for Pediatric Accidental Unsupervised Ingestions of Acetaminophen after the Introduction of Flow Restrictors

To assess the temporal association of flow restrictor introduction and the rate of accidental unsupervised ingestions (AUIs) of liquid acetaminophen products.

https://ift.tt/2Gvqsf4

Introduction to the TSJ special issue on interdisciplinary spine

Publication date: Available online 2 April 2018
Source:The Spine Journal
Author(s): Gregory L. Whitcomb




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O-1-13. Diagnosis of lumbar radiculopathy using magnetospinography

We previously reported noninvasive visualization of neural activities in the lumbar spine using magnetospinography (MSG). We report here MSG findings of a patient with lumbar radiculopathy.

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The Dantastic Mr Tox & Howard Episode 1 – Primum, Non Nocere

A discussion of the ongoing opioid epidemic.

EMCrit Project by Tox & Hound.

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Separation of Aldehydes and Reactive Ketones from Mixtures Using a Bisulfite Extraction Protocol

Here, we present a protocol to remove aldehydes and reactive ketones from mixtures by a liquid-liquid extraction protocol directly with saturated sodium bisulfite in a miscible solvent. This combined protocol is rapid and facile to perform. The aldehyde or ketone can be re-isolated by the basification of the aqueous layer.

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Issue Cover (April 2018)

European Journal of Neuroscience, Volume 47, Issue 7, Page i-iii, April 2018.


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Aging‐related prognosis analysis of definitive radiotherapy for very elderly esophageal cancer

Cancer Medicine, EarlyView.


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Umwelt and Ape Language Experiments: on the Role of Iconicity in the Human-Ape Pidgin Language

Abstract

Several language experiments have been carried out on apes and other animals aiming to narrow down the presumed qualitative gap that separates humans from other animals. These experiments, however, have been driven by the understanding of language as a purely symbolic sign system, often connected to a profound disinterest for language use in real situations and a propensity to perceive grammatical and syntactic information as the only fundamental aspects of human language. For these reasons, the language taught to apes tends to discard iconic and indexical elements in favour of symbolic signs. This paper sheds light on the iconic components of human language, with close attention to the iconic properties of language as present in the ape language experiments. We emphasise the role of the body in the interpretation and production of iconic signs, while demonstrating the need to take into account the Umwelt theory in the research paradigm of the experiments. Uexküll's Umwelt theory is used to exemplify the methodological problems connected to the teaching of human language to other animal species; furthermore, we discuss how the modelling capacities of language affect the biological layer that constitutes the animal Umwelt. Language is analysed as a particular case of Umwelt transition (Tønnessen), and as such its implications are further discussed in the article. With this paper, we enrich the discussion surrounding the human-ape pidgin language by advocating for the need to include iconic components as vital parts of this research area. With this inclusion, we uncover the inter-dependency of iconic, indexical and symbolic signs in human language, aiming to further develop the research paradigm of the ape language experiments.

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