Defining the value of magnetic resonance imaging in prostate brachytherapy using time-driven activity-based costing

Publication date: Available online 8 February 2017
Source:Brachytherapy
Author(s): Nikhil G. Thaker, Peter F. Orio, Louis Potters
Magnetic resonance imaging (MRI) simulation and planning for prostate brachytherapy (PBT) may deliver potential clinical benefits but at an unknown cost to the provider and healthcare system. Time-driven activity-based costing (TDABC) is an innovative bottom-up costing tool in healthcare that can be used to measure the actual consumption of resources required over the full cycle of care. TDABC analysis was conducted to compare patient-level costs for an MRI-based versus traditional PBT workflow. TDABC cost was only 1% higher for the MRI-based workflow, and utilization of MRI allowed for cost shifting from other imaging modalities, such as CT and ultrasound, to MRI during the PBT process. Future initiatives will be required to follow the costs of care over longer periods of time to determine if improvements in outcomes and toxicities with an MRI-based approach lead to lower resource utilization and spending over the long-term. Understanding provider costs will become important as healthcare reform transitions to value-based purchasing and other alternative payment models.



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Enhanced high-energy protocol using a fractional bipolar radiofrequency device combined with bipolar radiofrequency and infrared light for improving facial skin appearance and wrinkles

Summary

Background

Fractional bipolar radiofrequency treatment and treatment with bipolar radiofrequency combined with infrared light have been shown in previous trials to safely and effectively improve the appearance of facial wrinkles.

Aims

To evaluate a high-energy protocol with combined bipolar radiofrequency and infrared light energies for improvement in photoaged facial skin.

Patients/Methods

Seventy-two patients presenting with mild to moderate facial wrinkles underwent a single full-face treatment (n=54) or two treatments (n=18) at 6-week intervals. Independent blinded assessment and investigator assessment were performed, using the Fitzpatrick Wrinkle and Elastosis Scale (0-9) and the Global Aesthetic Improvement scale. Patients also completed a self-assessment questionnaire concerning satisfaction with the treatment.

Results

All patients achieved some degree of improvement in their wrinkles and skin appearance, following a single treatment or two treatments with the enhanced-energy protocol. Blinded evaluation demonstrated 71% and 70% of the patients showing improvement of one unit or greater on the Fitzpatrick Scale, at the 12-week and 24-week follow-ups post-treatment, respectively. Similar results were reported by investigators. Under the Global Aesthetic Improvement Scale, investigators observed 87%, 91% and 81% of patients showing improvement at the 6-, 12-, and 24-week post-treatment end, respectively. Patients tolerated the treatments well and were satisfied with the clinical results.

Conclusion

The enhanced-energy treatment protocol, with fractional bipolar radiofrequency treatment and treatment with bipolar radiofrequency combined with infrared light applications, yields significant improvement of skin texture, wrinkling, and overall appearance following a single treatment. The results appear gradually over time and are maintained for at least 6 months' post-treatment.

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China’s landscape in regenerative medicine

Publication date: April 2017
Source:Biomaterials, Volume 124
Author(s): Xin Tang, Hua Qin, Xiaosong Gu, Xiaobing Fu
Regenerative medicine is a burgeoning interdisciplinary research field that can impact healthcare by offering new therapeutic strategies to replace or regenerate human cells, tissues, or organs with the ultimate goal of restoring or establishing normal human functions. The past decade has seen significant progress of regenerative medicine in China, the world's most populous developing country. With government backing, the progress in regenerative medicine is driven by increasing medical demands of people, accompanied by the economic growth, population aging, and lifestyle change in China. Although regenerative medicine encompasses many components, tissue engineering and stem cell technology are generally considered the two key players. In this review article, we outline the representative achievements in the research and application of tissue engineering, stem cell technology, and other regenerative medical strategies attained by various research groups in China, and highlight the major contributions and features of several outstanding studies made by leading Chinese researchers. Where possible, we discuss the unique opportunities and challenges for advancement of regenerative medicine in China. It is our hope that this review will stimulate new research directions for regenerative medicine in general, and encourage strategic collaborations between the east and the west in particular, so that the clinical translation of regenerative medicine can be accelerated to benefit mankind.



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Development of ciprofloxacin-loaded contact lenses using fluorous chemistry

Publication date: April 2017
Source:Biomaterials, Volume 124
Author(s): Guoting Qin, Zhiling Zhu, Siheng Li, Alison M. McDermott, Chengzhi Cai
In this work, we developed a simple method to load drugs into commercially available contact lenses utilizing fluorous chemistry. We demonstrated this method using model compounds including fluorous-tagged fluorescein and antibiotic ciprofloxacin. We showed that fluorous interactions facilitated the loading of model molecules into fluorocarbon-containing contact lenses, and that the release profiles exhibited sustained release. Contact lenses loaded with fluorous-tagged ciprofloxacin exhibited antimicrobial activity against Pseudomonas aeruginosa in vitro, while no cytotoxicity towards human corneal epithelial cells was observed. To mimic the tear turnover, we designed a porcine eye infection model under flow conditions. Significantly, the modified lenses also exhibited antimicrobial efficacy against Pseudomonas aeruginosa in the ex vivo infection model. Overall, utilizing fluorous chemistry, we can construct a drug delivery system that exhibits high drug loading capacity, sustained drug release, and robust biological activity.



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Dual delivery of growth factors with coacervate-coated poly(lactic-co-glycolic acid) nanofiber improves neovascularization in a mouse skin flap model

Publication date: April 2017
Source:Biomaterials, Volume 124
Author(s): Min Suk Lee, Taufiq Ahmad, Jinkyu Lee, Hassan K. Awada, Yadong Wang, Kyobum Kim, Heungsoo Shin, Hee Seok Yang
Random skin flaps are commonly used in plastic and reconstructive surgery for patients suffering from severe or large scale wounds or in facial reconstruction. However, skin flaps are sometimes susceptible to partial or complete necrosis at the distal parts of the flaps due to insufficient blood perfusion in the defected area. In order to improve neovascularization in skin flaps, we developed an exogenous growth factor (GF) delivery platform comprised of coacervate-coated poly(lactic-co-glycolic acid) (PLGA) nanofibers. We used a coacervate that is a self-assembled complex of poly(ethylene argininyl aspartate diglyceride) (PEAD) polycation, heparin, and cargo GFs (i.e., vascular endothelial growth factor (VEGF) and/or transforming growth factor beta 3 (TGF-β3)). The coacervate was coated onto a nanofibrous PLGA membrane for co-administration of dual GFs. In vitro proliferation of human dermal fibroblasts and endothelial tube formation using human umbilical vein endothelial cells indicated an enhanced bioactivity of released GFs when both VEGF and TGF-β3 were incorporated into coacervate-coated PLGA nanofibers (Coa-Dual NFs). Moreover, an in vivo study using a mouse skin flap model demonstrated that implantation of Coa-Dual NF reduced necrosis and enhanced blood perfusion in skin flap areas after 10 days, as compared to any single GF-loaded coacervate/PLGA fiber (Coa-Single NF) along with direct administration of the other GF onto the defect site. Moreover, Coa-Dual NFs exhibited a well-composed skin appendage and a significantly higher number of blood vessels. Based upon these results, we conclude that Coa-Dual NFs may stimulate cellular activity by enhancing the bioactivity of the released GF, leading to a synergetic effect of dual GFs for reducing necrosis in the random skin flaps. Therefore, Coa-Dual NFs could be a valuable drug delivery platform for a variety of potential clinical applications for skin tissue regeneration applications.



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Evaluation of multivalent H2 influenza pandemic vaccines in mice

Publication date: Available online 8 February 2017
Source:Vaccine
Author(s): Brian J. Lenny, Stephanie Sonnberg, Angela F. Danner, Kimberly Friedman, Richard J. Webby, Robert G. Webster, Jeremy C. Jones
Subtype H2 Influenza A viruses were the cause of a severe pandemic in the winter of 1957. However, this subtype no longer circulates in humans and is no longer included in seasonal vaccines. As a result, individuals under 50years of age are immunologically naïve. H2 viruses persist in aquatic birds, which were a contributing source for the 1957 pandemic, and have also been isolated from swine. Reintroduction of the H2 via zoonotic transmission has been identified as a pandemic risk, so pre-pandemic planning should include preparation and testing of vaccine candidates against this subtype. We evaluated the immunogenicity of two inactivated, whole virus influenza vaccines (IVV) in mice: a monovalent IVV containing human pandemic virus A/Singapore/1/1957 (H2N2), and a multivalent IVV containing human A/Singapore/1/1957, avian A/Duck/HongKong/319/1978 (H2N2), and swine A/Swine/Missouri/2124514/2006 (H2N3) viruses. While both vaccines induced protective immunity compared to naïve animals, the multivalent formulation was advantageous over the monovalent in terms of level and breadth of serological responses, neutralization of infectious virus, and reduction of clinical disease and respiratory tissue replication in mice. Therefore, multivalent pandemic H2 vaccines containing diverse viruses from animal reservoirs, are a potential option to improve the immune responses in a pre-pandemic scenario where antigenic identity cannot be predicted.



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Glutathione is a highly efficient thermostabilizer of poliovirus Sabin strains

Publication date: Available online 8 February 2017
Source:Vaccine
Author(s): Rana Abdelnabi, Leen Delang, Johan Neyts
Glutathione (GSH) is the most abundant thiol peptide in animal cells and has a critical role in antioxidation. GSH was reported to be essential for stabilization of some enteroviruses, including poliovirus (PV), during viral morphogenesis. Here, we explored the potential use of GSH as a thermostabilizer of oral poliomyelitis vaccine (OPV) formulations. GSH significantly protected the three types of PV from heat-inactivation in a concentration-dependent manner. At a GSH concentration of 20mM, nearly complete protection was observed against heating temperatures up to 53°C for 2min.GSH also markedly protected PV1 from heat-inactivation and this up to 6 h at temperatures of 44°C and 46°C and 3 h at 48°C. The fact that GSH is naturally present at high concentration in the human body makes it an efficient candidate stabilizer for OPV formulations.



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Heritability of vaccine-induced measles neutralizing antibody titers

Publication date: Available online 8 February 2017
Source:Vaccine
Author(s): Daniel J. Schaid, Iana H. Haralambieva, Beth R. Larrabee, Inna G. Ovsyannikova, Richard B. Kennedy, Gregory A. Poland
Understanding how genetics influences inter-individual variation of antibody titers in response to measles vaccination is vital to understanding possible sources of vaccine failure as well as improved vaccine development. Although it is recognized that both the human leukocyte antigen (HLA) genes and the immunoglobulin allotype genes play significant roles in immune response, there is significant variation in antibody titers that is not explained by these genes. To obtain a more complete estimate of the role of the entire genome, we used a large panel of single nucleotide polymorphisms to estimate the heritability of antibody response to measles vaccine. Based on 935 subjects with European ancestry, we estimated the heritability to be 49% (standard error 0.17). We also estimated the heritability attributable to each chromosome, and found a large range in chromosome-specific heritabilities. Notably, chromosome 1 had the largest estimate (28%), while chromosome 6, which harbors HLA, had an estimated heritability of 13%. Compared with a prior study of twins in the same community, which resulted in a heritability estimate of 88.5%, our study suggests there are either many rare genetic variants, or many common genetic variants of small effect sizes that contribute to variations of antibody titers in response to measles vaccine.



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Vial usage, device dead space, vaccine wastage, and dose accuracy of intradermal delivery devices for inactivated poliovirus vaccine (IPV)

Publication date: Available online 8 February 2017
Source:Vaccine
Author(s): Courtney Jarrahian, Annie Rein-Weston, Gene Saxon, Ben Creelman, Greg Kachmarik, Abhijeet Anand, Darin Zehrung
IntroductionIntradermal delivery of a fractional dose of inactivated poliovirus vaccine (IPV) offers potential benefits compared to intramuscular (IM) delivery, including possible cost reductions and easing of IPV supply shortages. Objectives of this study were to assess intradermal delivery devices for dead space, wastage generated by the filling process, dose accuracy, and total number of doses that can be delivered per vial.MethodsDevices tested included syringes with staked (fixed) needles (autodisable syringes and syringes used with intradermal adapters), a luer-slip needle and syringe, a mini-needle syringe, a hollow microneedle device, and disposable-syringe jet injectors with their associated filling adapters. Each device was used to withdraw 0.1-mL fractional doses from single-dose IM glass vials which were then ejected into a beaker. Both vial and device were weighed before and after filling and again after expulsion of liquid to record change in volume at each stage of the process. Data were used to calculate the number of doses that could potentially be obtained from multidose vials.ResultsResults show wide variability in dead space, dose accuracy, overall wastage, and total number of doses that can be obtained per vial among intradermal delivery devices. Syringes with staked needles had relatively low dead space and low overall wastage, and could achieve a greater number of doses per vial compared to syringes with a detachable luer-slip needle. Of the disposable-syringe jet injectors tested, one was comparable to syringes with staked needles.DiscussionIf intradermal delivery of IPV is introduced, selection of an intradermal delivery device can have a substantial impact on vaccine wasted during administration, and thus on the required quantity of vaccine that needs to be purchased. An ideal intradermal delivery device should be not only safe, reliable, accurate, and acceptable to users and vaccine recipients, but should also have low dead space, high dose accuracy, and low overall wastage to maximize the potential number of doses that can be withdrawn and delivered.



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Role of Rho-specific guanine nucleotide dissociation inhibitor α regulation in cell migration

Publication date: Available online 8 February 2017
Source:Acta Histochemica
Author(s): Fei Xie, Shuai Shao, Aziz ur Rehman Aziz, Baohong Zhang, Hanqin Wang, Bo Liu
Cell migration is a vital process for many physiological and pathological events, and Rho GTPases have been confirmed as key factors in its regulation. The most studied negative regulator of Rho GTPases, Rho-specific guanine nucleotide dissociation inhibitor α (RhoGDIα), mediates cell migration through altering the overall expression and spatiotemporal activation of Rho GTPases. The RhoGDIα-Rho GTPases dissociation can be mediated by signal pathways targeting RhoGDIα directly. This review summarizes the research about the regulation of RhoGDIα during cell migration, which can be in a Rho GTPases association independent manner. Non-kinase proteins regulation, phosphorylation, SUMOylation and extracellular environmental factors are classified to discuss their direct signal regulations on RhoGDIα, which provide varied signal pathways for selective activation of Rho GTPases in cell migration.



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Nano-on-micro fibrous extracellular matrices for scalable expansion of human ES/iPS cells

Publication date: April 2017
Source:Biomaterials, Volume 124
Author(s): Li Liu, Ken-ichiro Kamei, Momoko Yoshioka, Minako Nakajima, Junjun Li, Nanae Fujimoto, Shiho Terada, Yumie Tokunaga, Yoshie Koyama, Hideki Sato, Kouichi Hasegawa, Norio Nakatsuji, Yong Chen
Human pluripotent stem cells (hPSCs) hold great potential for industrial and clinical applications. Clinical-grade scaffolds and high-quality hPSCs are required for cell expansion as well as easy handling and manipulation of the products. Current hPSC culture methods do not fulfill these requirements because of a lack of proper extracellular matrices (ECMs) and cell culture wares. We developed a layered nano-on-micro fibrous cellular matrix mimicking ECM, named "fiber-on-fiber (FF)" matrix, which enables easy handling and manipulation of cultured cells. While non-woven sheets of cellulose and polyglycolic acid were used as a microfiber layer facilitating mechanical stability, electrospun gelatin nanofibers were crosslinked on the microfiber layer, generating a mesh structure with connected nanofibers facilitating cell adhesion and growth. Our results showed that the FF matrix supports effective hPSC culture with maintenance of their pluripotency and normal chromosomes over two months, as well as effective scaled-up expansion, with fold increases of 54.1 ± 15.6 and 40.4 ± 8.4 in cell number per week for H1 human embryonic stem cells and 253G1 human induced pluripotent stem cells, respectively. This simple approach to mimick the ECM may have important implications after further optimization to generate lineage-specific products.



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Shape-controlled fabrication of magnetite silver hybrid nanoparticles with high performance magnetic hyperthermia

Publication date: April 2017
Source:Biomaterials, Volume 124
Author(s): Qi Ding, Dongfang Liu, Dawei Guo, Fang Yang, Xingyun Pang, Renchao Che, Naizhen Zhou, Jun Xie, Jianfei Sun, Zhihai Huang, Ning Gu
Superparamagnetic Fe3O4 nanoparticles (NPs)-based hyperthermia is a promising non-invasive approach for cancer therapy. However, the heat transfer efficiency of Fe3O4 NPs is relative low, which hinders their practical clinical applications. Therefore, it is promising to improve the magnetic hyperthermia efficiency by exploring the higher performance magnetic NPs-based hybrid nanostructures. In the current study, it presents a straightforward in situ reduction method for the shape-controlled preparation of magnetite (Fe3O4) silver (Ag) hybrid NPs designed as magnetic hyperthermia heat mediators. The magnetite silver hybrid NPs with core-shell (Fe3O4@Ag) or heteromer (Fe3O4-Ag) structures exhibited a higher biocompatibility with SMMC-7721 cells and L02 cells than the individual Ag NPs. Importantly, in the magnetic hyperthermia, with the exposure to alternating current magnetic field, the Fe3O4@Ag and Fe3O4-Ag hybrid NPs indicated much better tumor suppression effect against SMMC-7721 cells than the individual Fe3O4 NPs in vitro and in vivo. These results demonstrate that the hybridisation of Fe3O4 and Ag NPs could greatly enhance the magnetic hyperthermia efficiency of Fe3O4 NPs. Therefore, the Fe3O4@Ag and Fe3O4-Ag hybrid NPs can be used to be as high performance magnetic hyperthermia mediators based on a simple and effective preparation approach.



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Antibacterial effects of titanium embedded with silver nanoparticles based on electron-transfer-induced reactive oxygen species

Publication date: April 2017
Source:Biomaterials, Volume 124
Author(s): Guomin Wang, Weihong Jin, Abdul Mateen Qasim, Ang Gao, Xiang Peng, Wan Li, Hongqing Feng, Paul K. Chu
Although titanium embedded with silver nanoparticles (Ag-NPs@Ti) are suitable for biomedical implants because of the good cytocompatibility and antibacterial characteristics, the exact antibacterial mechanism is not well understood. In the present work, the antibacterial mechanisms of Ag-NPs@Ti prepared by plasma immersion ion implantation (PIII) are explored in details. The antibacterial effects of the Ag-NPs depend on the conductivity of the substrate revealing the importance of electron transfer in the antibacterial process. In addition, electron transfer between the Ag-NPs and titanium substrate produces bursts of reactive oxygen species (ROS) in both the bacteria cells and culture medium. ROS leads to bacteria death by inducing intracellular oxidation, membrane potential variation, and cellular contents release and the antibacterial ability of Ag-NPs@Ti is inhibited appreciably after adding ROS scavengers. Even though ROS signals are detected from osteoblasts cultured on Ag-NPs@Ti, the cell compatibility is not impaired. This electron-transfer-based antibacterial process which produces ROS provides insights into the design of biomaterials with both antibacterial properties and cytocompatibility.



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Inhibitory deficits in prepulse inhibition, sensory gating, and antisaccade eye movement in schizotypy

Publication date: Available online 8 February 2017
Source:International Journal of Psychophysiology
Author(s): Li Wan, Zachary Thomas, Sindhura Pisipati, Stephen P. Jarvis, Nash N. Boutros
Schizotypy is a term that refers to a continuum of personality characteristics, emerging from mental states ranging from organized and normal to unorganized and disordered; with the latter tending to include individuals with high schizotypal scores as well as those diagnosed with schizotypal personality disorder. Evidence from psychophysiological studies has found a relative weakness in the inhibitory functioning, including prepulse inhibition (PPI), sensory gating (SG), and antisaccade eye movement (AEM) in schizotypy and schizophrenia. As schizotypy and schizophrenia are in the same spectrum, understanding the nature of sensory and motor inhibitory weakness associated with schizotypy will optimize the prevention and intervention for both schizotypy and schizophrenia populations.This review aims at examining the deficits of sensory gating, saccade control, and prepulse inhibition in schizotypy; examining the relationship between the three measures and schizotypal symptoms and traits; examining the effect of nicotine on the three measures; and examining the relevant brain regions to the three measures. We searched multiple databases (such as MEDLINE, Pubmed, PsychINFO, Google Scholar) using combinations of the keywords: schizotypy, schizotypal personality disorder, prepulse inhibition, sensory gating and antisaccade for articles published in English since 1980.We found that three measures (SG, PPI and AEM) are associated with major schizotypal symptoms, suggesting that three measures could be used to predict the disease etiology and prognosis. Secondly, the three measures are modulated by nicotine administration at a certain level, providing a potential tool to study the role of nicotine in the cognition and symptom improvement in schizotypy. Thirdly, brain-imaging studies have localized activity in brain regions associated with sensory gating, saccade control, and prepulse inhibition, narrowing the search for brain regions to target for the treatment and prevention of schizotypy. Overall, the three measures are suggested to be a valuable tool to study the inhibitory deficits in schizotypy, and maybe used as a tool for the prevention and treatment of schizotypy as well.



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Multitarget sensing of glucose and cholesterol based on Janus hydrogel microparticles

Publication date: 15 June 2017
Source:Biosensors and Bioelectronics, Volume 92
Author(s): Xiao-Ting Sun, Ying Zhang, Dong-Hua Zheng, Shuai Yue, Chun-Guang Yang, Zhang-Run Xu
A visualized sensing method for glucose and cholesterol was developed based on the hemispheres of the same Janus hydrogel microparticles. Single-phase and Janus hydrogel microparticles were both generated using a centrifugal microfluidic chip. For glucose sensing, concanavalin A and fluorescein labeled dextran used for competitive binding assay were encapsulated in alginate microparticles, and the fluorescence of the microparticles was positively correlated with glucose concentration. For cholesterol sensing, the microparticles embedded with γ-Fe2O3 nanoparticles were used as catalyst for the oxidation of 3,3′,5,5′-Tetramethylbenzidine by H2O2, an enzymatic hydrolysis product of cholesterol. And the color transition was more sensitive in the microparticles than in solutions, indicating the microparticles are more applicable for visualized determination. Furthermore, Janus microparticles were employed for multitarget sensing in the two hemespheres, and glucose and cholesterol were detected within the same microparticles without obvious interference. Besides, the particles could be manipulated by an external magnetic field. The glucose and cholesterol levels were measured in human serum utilizing the microparticles, which confirmed the potential application of the microparticles in real sample detection.



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Regulation of aldosterone secretion by mineralocorticoid receptor-mediated signaling

We posit the existence of a paracrine/autocrine negative feedback loop, mediated by the mineralocorticoid receptor (MR), regulating aldosterone secretion. To assess this hypothesis, we asked whether altering MR activity in zona glomerulosa (ZG) cells affects aldosterone production. To this end, we studied ex vivo ZG cells isolated from male Wistar rats fed chow containing either high (1.6% Na⁺ (HS)) or low (0.03% Na⁺ (LS)) amount of sodium. Western blot analyses demonstrated that MR was present in both the ZG and zona fasciculata/zona reticularis (ZF/ZR/ZR). In ZG cells isolated from rats on LS chow, MR activation by fludrocortisone produced a 20% and 60% reduction in aldosterone secretion basally and in response to angiotensin II (ANGII) stimulation, respectively. Corticosterone secretion was increased in these cells suggesting that aldosterone synthase activity was being reduced by fludrocortisone. In contrast, canrenoic acid, an MR antagonist, enhanced aldosterone production by up to 30% both basally and in response to ANGII. Similar responses were observed in ZG cells from rats fed HS. Modulating glucocorticoid receptor (GR) activity did not alter aldosterone production by ZG cells; however, altering GR activity did modify corticosterone production from ZF/ZR/ZR cells both basally and in response to adrenocorticotropic hormone (ACTH). Additionally, activating the MR in ZF/ZR/ZR cells strikingly reduced corticosterone secretion. In summary, these data support the hypothesis that negative ultra-short feedback loops regulate adrenal steroidogenesis. In the ZG, aldosterone secretion is regulated by the MR, but not the GR, an effect that appears to be secondary to a change in aldosterone synthase activity.

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Key Lessons Learned from Moffitt's Molecular Tumor Board: The Clinical Genomics Action Committee Experience

Background.

The increasing practicality of genomic sequencing technology has led to its incorporation into routine clinical practice. Successful identification and targeting of driver genomic alterations that provide proliferative and survival advantages to tumor cells have led to approval and ongoing development of several targeted cancer therapies. Within many major cancer centers, molecular tumor boards are constituted to shepherd precision medicine into clinical practice.

Materials and Methods

In July 2014, the Clinical Genomics Action Committee (CGAC) was established as the molecular tumor board companion to the Personalized Medicine Clinical Service (PMCS) at Moffitt Cancer Center in Tampa, Florida. The processes and outcomes of the program were assessed in order to help others move into the practice of precision medicine.

Results.

Through the establishment and initial 1,400 patients of the PMCS and its associated molecular tumor board at a major cancer center, five practical lessons of broad applicability have been learned: transdisciplinary engagement, the use of the molecular report as an aid to clinical management, clinical actionability, getting therapeutic options to patients, and financial considerations. Value to patients includes access to cutting-edge practice merged with individualized preferences in treatment and care.

Conclusions.

Genomic-driven cancer medicine is increasingly becoming a part of routine clinical practice. For successful implementation of precision cancer medicine, strategically organized molecular tumor boards are critical to provide objective evidence-based translation of observed molecular alterations into patient-centered clinical action. Molecular tumor board implementation models along with clinical and economic outcomes will define future treatment standards. The Oncologist 2017;22:000–000

Implications for Practice: It is clear that the increasing practicality of genetic tumor sequencing technology has led to its incorporation as part of routine clinical practice. Subsequently, many cancer centers are seeking to develop a personalized medicine services and/or molecular tumor board to shepherd precision medicine into clinical practice. This article discusses the key lessons learned through the establishment and development of a molecular tumor board and personalized medicine clinical service. This article highlights practical issues and can serve as an important guide to other centers as they conceive and develop their own personalized medicine services and molecular tumor boards.

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Association Between Tumor Progression Endpoints and Overall Survival in Patients with Advanced Neuroendocrine Tumors

Endpoints related to tumor progression are commonly used in clinical trials of novel therapeutic agents for neuroendocrine tumors (NETs). Whether improved tumor control translates into improved overall survival (OS), however, is uncertain. We assessed associations between tumor progression endpoints and OS in observational cohorts of patients with advanced neuroendocrine tumors treated with somatostatin analogs or with everolimus. We identified 440 patients with advanced NET who had received treatment with single-agent somatostatin analogs and 109 patients treated with everolimus, all of whom were treated at our institution and were evaluable for both tumor progression and survival. We assessed associations between progression-free survival (PFS) and OS by using the Kendall tau test, and we assessed associations between tumor progression and OS by using a landmark analysis. In the 440 patients treated with somatostatin analogs, we observed a significant correlation between PFS and OS by using the Kendall tau test (0.31; p < .0001). Additionally, the development of progressive disease was associated with OS in a landmark analysis, at landmark times of 6, 12, 18, and 24 months. In the 109 patients treated with everolimus, we similarly observed a significant correlation between PFS and OS by using the Kendall tau test (0.44; p < .0001) and associations between progressive disease and OS by using a landmark analysis at 3, 6, and 12 months. In these observational cohorts of patients with metastatic NET treated with single-agent somatostatin analogs or everolimus, longer times to disease progression and longer PFS were both associated with improved OS. Our findings support the continued use of disease progression endpoints in NET clinical trials. The Oncologist 2017;22:000–000

Implications for Practice: Clinical trials in patients with advanced neuroendocrine tumors have used progression-free survival as a primary endpoint. While there is a general assumption that slowing or halting tumor growth is beneficial, little direct evidence links improvements in progression endpoints to improvements in overall survival. This study assessed associations between tumor progression endpoints and overall survival in observational cohorts of patients with advanced neuroendocrine tumor treated with somatostatin analogs or everolimus. Longer times to disease progression and improved progression-free survival were both associated with improved overall survival. The findings support the continued use of tumor progression endpoints in clinical trials for neuroendocrine tumors.

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Radiology Education of Physician Extenders: What Role Should Radiologists Play?

Publication date: Available online 8 February 2017
Source:Academic Radiology
Author(s): Jamie L. RiChard, Benjamin P. Liu, David D. Casalino, Eric J. Russell, Jeanne M. Horowitz
As physician extenders (PEs) enter the medical community in large numbers, they have an increasing impact on imaging utilization and imaging-based procedures. Physician assistants (PAs) and nurse practitioners (NPs) have an advanced level of education and some practice autonomously. However, PA and NP programs are not required to provide any basic radiology education. For PEs who did receive basic radiology education during their graduate program, the curriculum is nonstandard and there is a wide variation. PEs working in primary care and nonradiology specialties place imaging orders, review report findings, and answer patient questions. Other PEs working within radiology practices operate as liaisons with patients in diagnostic radiology or perform an increasing number of interventional procedures. Basic radiology education in formal PE certificate programs as well as on-the-job education about radiology may benefit patients, radiologists, and the health-care system. What role, if any, should the radiologist assume for educating PE students and practicing PAs and NPs? This review analyzes the benefits and drawbacks of radiologists educating PEs.



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Radiology-Pathology Conference: Reviving the Art of Oral Case Presentation in Residency

Publication date: Available online 8 February 2017
Source:Academic Radiology
Author(s): Susan Sotardi, Meir H. Scheinfeld, Judah Burns, Mordecai Koenigsberg, Jose G. Mantilla, Shlomit Goldberg-Stein
Rationale and ObjectivesTo improve resident oral case communication and preparatory skills by providing residents an opportunity to prepare for and conduct a new interdisciplinary Radiology-Pathology (Rad-Path) conference series.Materials and MethodsTo assess whether conference goals were being achieved, we surveyed trainees and attendings in the radiology and pathology departments. Percentages were examined for each variable. Mann-Whitney U test for ordinal variable significance was applied to determine statistical significance between radiology trainee and attending survey responses.ResultsMost surveyed radiology trainees (57.1%) strongly agreed or agreed with: "I wish I felt more comfortable with oral presentations." Sixty-five percent of radiology attendings (34 of 52) either agreed or strongly agreed that the residents should be more comfortable with oral case presentations. Of resident Rad-Path conference presenters, 69% (9 of 13) either agreed or strongly agreed that the conference improved their confidence and/or ability to present case information orally. Of responders who attended at least one Rad-Path conference in person, 83% of residents (19/23) and 61% (17/28) of attendings agreed or strongly agreed that the conference improved their ability to formulate a differential diagnosis. Using the Mann-Whitney U test, no significant difference was found between radiology trainees and attendings' responses.ConclusionsOur Rad-Path correlation conference was specifically designed and structured to provide residents with focused experience in formal oral case preparation and presentation. We consider our conference a success, with 69% of resident presenters reporting that the Rad-Path conference improved their confidence and/or ability to present case information orally.



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How Does the Display Luminance Level Affect Detectability of Breast Microcalcifications and Spiculated Lesions in Digital Breast Tomosynthesis (DBT) Images?

Publication date: Available online 8 February 2017
Source:Academic Radiology
Author(s): Claudio Ferranti, Alessandra Primolevo, Francesco Cartia, Claudia Cavatorta, Chiara Maura Ciniselli, Manuela Lualdi, Silvia Meroni, Emanuele Pignoli, Maddalena Plebani, Claudio Siciliano, Paolo Verderio, Gianfranco Scaperrotta
Rationale and ObjectivesThis study evaluates the influence of the calibrated luminance level of medical displays in the detectability of microcalcifications and spiculated lesions in digital breast tomosynthesis images.Materials and MethodsFour models of medical displays with calibrated maximum and minimum luminance, respectively, ranging from 500 to 1000 cd/m² and from 0.5 to 1.0 cd/m², were investigated. Forty-eight studies were selected by a senior radiologist: 16 with microcalcifications, 16 with spiculated lesions, and 16 without lesions. All images were anonymized and blindly evaluated by one senior and two junior radiologists. For each study, lesion presence or absence and localization statements, interpretative difficulty level, and overall quality were reported. Cohen's kappa statistic was computed between monitors and within or between radiologists to estimate the reproducibility in correctly identifying lesions; for multireader-multicase analysis, the weighted jackknife alternative free-response receiver operating characteristic statistical tool was applied.ResultsIntraradiologist reproducibility ranged from 0.75 to 1.00. Interreader as well as reader-truth agreement values were >0.80 and higher with the two 1000 cd/m² luminance displays than with the lower luminance displays for each radiologist. Performances in the detectability of breast lesions were significantly greater with the 1000 cd/m² luminance displays when compared to the display with the lowest luminance value (P value <0.001).ConclusionsOur findings highlight the role of display luminance level on the accuracy of detecting breast lesions.



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Missteps in Estimates of Cancer Overdiagnosis

Publication date: Available online 8 February 2017
Source:Academic Radiology
Author(s): Archie Bleyer




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Cysteine-based amphiphilic peptide-polymer conjugates via thiol-mediated radical polymerization: Synthesis, self-assembly, RNA polyplexation and N-terminus fluorescent labeling for cell imaging

Publication date: 10 March 2017
Source:Polymer, Volume 112
Author(s): Madhab Dule, Mrinmoy Biswas, Yajnaseni Biswas, Kuheli Mandal, Nikhil R. Jana, Tarun K. Mandal
A water-soluble amphiphilic peptide-poly (1-vinylimidazole) [Boc-Cys (PVim)-Trp-OMe] bioconjugate is synthesized by 'grafting from' technique based on thiol-mediated radical polymerization. The attachment of fluorescein isothiocyanate (FITC) at the N-terminus of the peptide moiety of the bioconjugate results in the generation of fluorescent bioconjugate [FITC-Cys (PVim)-Trp-OMe]. MALDI-TOF-MS analysis confirms the attachment dipeptide moiety as well as FITC group. Owing to the amphiphilic nature, the [Boc-Cys (PVim)-Trp-OMe] bioconjugate undergoes spontaneous self-assembly into primary micelles and their subsequent secondary aggregation into spherical micellar aggregates (nanospheres) in water. The aqueous FITC-Cys (PVim)-Trp-OMe bioconjugate solution emits green light and exhibits a fluorescence emission with a maximum at 520 nm. The amphiphilicity of the fluorescent bioconjuagte molecules also triggers their self-assembly into micelles and micellar aggregates (nanospheres) with hydrophobic FITC-tagged dipeptide core and hydrophilic PVim cell in water. Further, the highly stable and non-toxic fluorescent bioconjugates are used for imaging of Chinese Hamster Ovary (CHO) cells. Finally, the polyplex formation between the untagged cationic Boc-Cys (PVim)-Trp-OMe bioconjugate and ribonucleic acid (RNA) at pH 5.5 is studied by fluorescence spectroscopy.

Graphical abstract

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A novel host-pathogen interaction potentially driving antibiotic resistance in livestock feedlots

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Vermicompost as a natural adsorbent: evaluation of simultaneous metals (Pb, Cd) and tetracycline adsorption by sewage sludge-derived vermicompost

Abstract

The simultaneous adsorption of heavy metals (Pb, Cd) and organic pollutant (tetracycline (TC)) by a sewage sludge-derived vermicompost was investigated. The maximal adsorption capacity for Pb, Cd, and TC in a single adsorptive system calculated from Langmuir equation was 12.80, 85.20, and 42.94 mg L⁻¹, while for mixed substances, the adsorption amount was 2.99, 13.46, and 20.89 mg L⁻¹, respectively. The adsorption kinetics fitted well to the pseudo-second-order model, implying chemical interaction between adsorbates and functional groups, such as –COOH, –OH, –NH, and –CO, as well as the formation of organo-metal complexes. Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and Brunauer–Emmett–Teller (BET) specific surface area measurement were adopted to gain insight into the structural changes and a better understanding of the adsorption mechanism. The sewage sludge-derived vermicompost can be a low cost and environmental benign eco-material for high efficient wastewater remediation.

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The CAT(2) Comes Back

Publication date: 8 February 2017
Source:Cell Host & Microbe, Volume 21, Issue 2
Author(s): Musoki Mwimba, Xinnian Dong
Genetic and biochemical evidence supporting CATALASE2 as a salicylic acid (SA) receptor has finally emerged. In this issue of Cell Host & Microbe, Yuan et al. (2017) show that SA binds to CATALASE2 to inhibit auxin and jasmonic acid biosynthetic enzymes as a means to strengthen plant immunity against biotrophic pathogens.

Teaser

Genetic and biochemical evidence supporting CATALASE2 as a salicylic acid (SA) receptor has finally emerged. In this issue of Cell Host & Microbe, Yuan et al. (2017) show that SA binds to CATALASE2 to inhibit auxin and jasmonic acid biosynthetic enzymes as a means to strengthen plant immunity against biotrophic pathogens.


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Strange New World: Bacteria Catalyze Ubiquitylation via ADP Ribosylation

Publication date: 8 February 2017
Source:Cell Host & Microbe, Volume 21, Issue 2
Author(s): David Komander, Felix Randow
Three recent papers, including one by Kotewicz et al. (2016) in this issue of Cell Host & Microbe, show that Legionella deploys a novel form of ubiquitylation to generate its replicative vacuole. Without E1 and E2 enzymes, SidE effectors ubiquitylate serine residues in substrates via an ADP-ribosylated ubiquitin intermediate.

Teaser

Three recent papers, including one by Kotewicz et al. in this issue of Cell Host & Microbe, show that Legionella deploys a novel form of ubiquitylation to generate its replicative vacuole. Without E1 and E2 enzymes, SidE effectors ubiquitylate serine residues in substrates via an ADP-ribosylated ubiquitin intermediate.


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Take Your Pick: Vitamins and Microbiota Facilitate Pathogen Clearance

Publication date: 8 February 2017
Source:Cell Host & Microbe, Volume 21, Issue 2
Author(s): Vanessa Sperandio
The gut microbiota plays a chief role in vitamin production. Changes in its membership impact the gut metabolome and host susceptibility to pathogens. In this issue of Cell Host & Microbe, Miki et al. (2017) show that RegIIIβ impacts microbiota composition, decreasing vitamin B6 production and promoting sustained colonization by Salmonella.

Teaser

The gut microbiota plays a chief role in vitamin production. Changes in its membership impact the gut metabolome and host susceptibility to pathogens. In this issue of Cell Host & Microbe, Miki et al. (2017) show that RegIIIβ impacts microbiota composition, decreasing vitamin B6 production and promoting sustained colonization by Salmonella.


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HO-2 Pockets Myristoylated Gag

Publication date: 8 February 2017
Source:Cell Host & Microbe, Volume 21, Issue 2
Author(s): Marilyn D. Resh
Membrane binding of viral and cellular N-myristoylated proteins can be regulated by selectively sequestering myristate. In this issue of Cell Host & Microbe, Zhu et al. (2017) report on a myristate binding site within the cellular protein heme oxygenase-2 that acts as a trap to inhibit N-myristoylated protein function.

Teaser

Membrane binding of viral and cellular N-myristoylated proteins can be regulated by selectively sequestering myristate. In this issue of Cell Host & Microbe, Zhu et al. (2017) report on a myristate binding site within the cellular protein heme oxygenase-2 that acts as a trap to inhibit N-myristoylated protein function.


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Zika Virus Pathogenesis and Tissue Tropism

Publication date: 8 February 2017
Source:Cell Host & Microbe, Volume 21, Issue 2
Author(s): Jonathan J. Miner, Michael S. Diamond
Although Zika virus (ZIKV) was isolated approximately 70 years ago, few experimental studies had been published prior to 2016. The recent spread of ZIKV to countries in the Western Hemisphere is associated with reports of microcephaly, congenital malformations, and Guillain-Barré syndrome. This has resulted in ZIKV being declared a public health emergency and has greatly accelerated the pace of ZIKV research and discovery. Within a short time period, useful mouse and non-human primate disease models have been established, and pre-clinical evaluation of therapeutics and vaccines has begun. Unexpectedly, ZIKV exhibits a broad tropism and persistence in body tissues and fluids, which contributes to the clinical manifestations and epidemiology that have been observed during the current epidemic. In this Review, we highlight recent advances in our understanding of ZIKV pathogenesis, tissue tropism, and the resulting pathology and discuss areas for future investigation.

Teaser

The recent outbreak of Zika virus (ZIKV) in the Western Hemisphere has prompted accelerated research and discovery in this area. Miner and Diamond review some of the key recent advances in our understanding of ZIKV pathogenesis, tissue tropism, and the resulting pathology and discuss areas for future investigation.


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CATALASE2 Coordinates SA-Mediated Repression of Both Auxin Accumulation and JA Biosynthesis in Plant Defenses

Publication date: 8 February 2017
Source:Cell Host & Microbe, Volume 21, Issue 2
Author(s): Hong-Mei Yuan, Wen-Cheng Liu, Ying-Tang Lu
Plants defend against pathogen attack by modulating auxin signaling and activating the salicylic acid (SA) and jasmonic acid (JA) signaling pathways. SA and JA act antagonistically in resistance to specific pathogen types, yet how plants coordinate these phytohormones remains elusive. Here we report that biotrophic-pathogen-induced SA accumulation dampens both auxin and JA synthesis by inhibiting CATALASE2 (CAT2) activity in the model plant Arabidopsis. SA suppression of CAT2 results in increased H2O2 levels and subsequent sulfenylation of tryptophan synthetase β subunit 1, thus depleting the auxin biosynthetic precursor tryptophan. In addition, we find that CAT2 promotes JA biosynthesis by facilitating direct interaction of the JA biosynthetic enzymes ACX2 and ACX3, and thus SA repression of CAT2 inhibits JA accumulation. As such, the cat2-1 mutant exhibits increased resistance to biotrophic pathogens and increased susceptibility to necrotrophic pathogens. Our study illustrates how CAT2 coordinates SA repression of auxin accumulation and JA biosynthesis in plant defense.

Graphical abstract

Teaser

Salicylic acid, jasmonic acid, and auxin function in plant defense responses against biotrophic and necrotrophic pathogens. How these phytohormones are coordinated in plant immunity remains elusive. Yuan et al. showed that CATALASE2 coordinates salicylic-acid-mediated repression of auxin and jasmonic acid biosynthesis in plant resistance to different pathogens.


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Pseudogenization of the Secreted Effector Gene sseI Confers Rapid Systemic Dissemination of S. Typhimurium ST313 within Migratory Dendritic Cells

Publication date: 8 February 2017
Source:Cell Host & Microbe, Volume 21, Issue 2
Author(s): Sarah E. Carden, Gregory T. Walker, Jared Honeycutt, Kyler Lugo, Trung Pham, Amanda Jacobson, Donna Bouley, Juliana Idoyaga, Renee M. Tsolis, Denise Monack
Genome degradation correlates with host adaptation and systemic disease in Salmonella. Most lineages of the S. enterica subspecies Typhimurium cause gastroenteritis in humans; however, the recently emerged ST313 lineage II pathovar commonly causes systemic bacteremia in sub-Saharan Africa. ST313 lineage II displays genome degradation compared to gastroenteritis-associated lineages; yet, the mechanisms and causal genetic differences mediating these infection phenotypes are largely unknown. We find that the ST313 isolate D23580 hyperdisseminates from the gut to systemic sites, such as the mesenteric lymph nodes (MLNs), via CD11b⁺ migratory dendritic cells (DCs). This hyperdissemination was facilitated by the loss of sseI, which encodes an effector that inhibits DC migration in gastroenteritis-associated isolates. Expressing functional SseI in D23580 reduced the number of infected migratory DCs and bacteria in the MLN. Our study reveals a mechanism linking pseudogenization of effectors with the evolution of niche adaptation in a bacterial pathogen.

Graphical abstract

Teaser

Genome degradation is associated with host adaptation in bacteria. Carden et al. show that the bacteremia-associated ST313 Salmonella Typhimurium lineage hyperdisseminates to systemic sites in mice compared to gastroenteritis-associated lineages. They demonstrate that pseudogenization of a single gene, sseI, contributes to hyperdissemination of ST313 isolates via infected DCs.


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Microbial Respiration and Formate Oxidation as Metabolic Signatures of Inflammation-Associated Dysbiosis

Publication date: 8 February 2017
Source:Cell Host & Microbe, Volume 21, Issue 2
Author(s): Elizabeth R. Hughes, Maria G. Winter, Breck A. Duerkop, Luisella Spiga, Tatiane Furtado de Carvalho, Wenhan Zhu, Caroline C. Gillis, Lisa Büttner, Madeline P. Smoot, Cassie L. Behrendt, Sara Cherry, Renato L. Santos, Lora V. Hooper, Sebastian E. Winter
Intestinal inflammation is frequently associated with an alteration of the gut microbiota, termed dysbiosis, which is characterized by a reduced abundance of obligate anaerobic bacteria and an expansion of facultative Proteobacteria such as commensal E. coli. The mechanisms enabling the outgrowth of Proteobacteria during inflammation are incompletely understood. Metagenomic sequencing revealed bacterial formate oxidation and aerobic respiration to be overrepresented metabolic pathways in a chemically induced murine model of colitis. Dysbiosis was accompanied by increased formate levels in the gut lumen. Formate was of microbial origin since no formate was detected in germ-free mice. Complementary studies using commensal E. coli strains as model organisms indicated that formate dehydrogenase and terminal oxidase genes provided a fitness advantage in murine models of colitis. In vivo, formate served as electron donor in conjunction with oxygen as the terminal electron acceptor. This work identifies bacterial formate oxidation and oxygen respiration as metabolic signatures for inflammation-associated dysbiosis.

Graphical abstract

Teaser

Intestinal inflammation is associated with changes in the microbiota composition (dysbiosis), such as the expansion of the commensal Enterobacteriaceae population. Hughes and Winter et al. show that utilization of microbiota-derived formate as electron donor and oxygen as terminal electron acceptor contribute to the bloom of Enterobacteriaceae in the inflamed gut.


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Conserved Fever Pathways across Vertebrates: A Herpesvirus Expressed Decoy TNF-α Receptor Delays Behavioral Fever in Fish

Publication date: 8 February 2017
Source:Cell Host & Microbe, Volume 21, Issue 2
Author(s): Krzysztof Rakus, Maygane Ronsmans, Maria Forlenza, Maxime Boutier, M. Carla Piazzon, Joanna Jazowiecka-Rakus, Derek Gatherer, Alekos Athanasiadis, Frédéric Farnir, Andrew J. Davison, Pierre Boudinot, Thomas Michiels, Geert F. Wiegertjes, Alain Vanderplasschen
Both endotherms and ectotherms (e.g., fish) increase their body temperature to limit pathogen infection. Ectotherms do so by moving to warmer places, hence the term "behavioral fever." We studied the manifestation of behavioral fever in the common carp infected by cyprinid herpesvirus 3, a native carp pathogen. Carp maintained at 24°C died from the infection, whereas those housed in multi-chamber tanks encompassing a 24°C–32°C gradient migrated transiently to the warmest compartment and survived as a consequence. Behavioral fever manifested only at advanced stages of infection. Consistent with this, expression of CyHV-3 ORF12, encoding a soluble decoy receptor for TNF-α, delayed the manifestation of behavioral fever and promoted CyHV-3 replication in the context of a temperature gradient. Injection of anti-TNF-α neutralizing antibodies suppressed behavioral fever, and decreased fish survival in response to infection. This study provides a unique example of how viruses have evolved to alter host behavior to increase fitness.

Graphical abstract

Teaser

Ectotherms can express behavioral fever to limit pathogen infection. Rakus et al. show that a carp herpesvirus delays behavioral fever by expressing a soluble decoy receptor for TNF-α, thus promoting its own replication. In addition, they demonstrate a role for TNF-α in the induction of behavioral fever in teleost fish.


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NEOSCOPE: A randomised phase II study of induction chemotherapy followed by oxaliplatin/capecitabine or carboplatin/paclitaxel based pre-operative chemoradiation for resectable oesophageal adenocarcinoma

Publication date: March 2017
Source:European Journal of Cancer, Volume 74
Author(s): Somnath Mukherjee, Christopher Nicholas Hurt, Sarah Gwynne, David Sebag-Montefiore, Ganesh Radhakrishna, Simon Gollins, Maria Hawkins, Heike I. Grabsch, Gareth Jones, Stephen Falk, Ricky Sharma, Andrew Bateman, Rajarshi Roy, Ruby Ray, Jo Canham, Gareth Griffiths, Tim Maughan, Tom Crosby
BackgroundOxaliplatin-capecitabine (OxCap) and carboplatin-paclitaxel (CarPac) based neo-adjuvant chemoradiotherapy (nCRT) have shown promising activity in localised, resectable oesophageal cancer.Patients and methodsA non-blinded, randomised (1:1 via a centralised computer system), 'pick a winner' phase II trial. Patients with resectable oesophageal adenocarcinoma ≥ cT3 and/or ≥ cN1 were randomised to OxCapRT (oxaliplatin 85 mg/m² day 1, 15, 29; capecitabine 625 mg/m² bd on days of radiotherapy) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m² day 1, 8, 15, 22, 29). Radiotherapy dose was 45 Gy/25 fractions/5 weeks. Both arms received induction OxCap chemotherapy (2 × 3 week cycles of oxaliplatin 130 mg/m² day 1, capecitabine 625 mg/m² bd days 1–21). Surgery was performed 6–8 weeks after nCRT. Primary end-point was pathological complete response (pCR). Secondary end-points included toxicity, surgical morbidity/mortality, resection rate and overall survival.StatisticsBased on pCR ≤ 15% not warranting future investigation, but pCR ≥ 35% would, 76 patients (38/arm) gave 90% power (one-sided alpha 10%), implying that arm(s) having ≥10 pCR out of first 38 patients could be considered for phase III trials. ClinicalTrials.gov: NCT01843829. Funder: Cancer Research UK (C44694/A14614).ResultsEighty five patients were randomised between October 2013 and February 2015 from 17 UK centres. Three of 85 (3.5%) died during induction chemotherapy. Seventy-seven patients (OxCapRT = 36; CarPacRT = 41) underwent surgery. The 30-d post-operative mortality was 2/77 (2.6%). Grade III/IV toxicity was comparable between arms, although neutropenia was higher in the CarPacRT arm (21.4% versus 2.6%, p = 0.01). Twelve of 41 (29.3%) (10 of first 38 patients) and 4/36 (11.1%) achieved pCR in the CarPacRT and OxcapRT arms, respectively. Corresponding R0 resection rates were 33/41 (80.5%) and 26/36 (72.2%), respectively.ConclusionBoth regimens were well tolerated. Only CarPacRT passed the predefined pCR criteria for further investigation.



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Response to the Reply to the letter to the editor “Robotic-assisted Nipple Sparing Mastectomy: A feasibility study on cadaveric models”

It was with great interest that we read the reply of Toesca et al. regarding our feasibility study on robotic nipple sparing mastectomy techniques on cadaveric models, especially their comments and advice.

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Treating submucous clefts with a double-opposing Z-plasty

Baek et al describe that the double-opposing Z-plasty could be a very valuable technique to treat hypernasality in submucous clefts1. Although this study is a valuable adjunct to the cleft literature, some factors need attention. The authors demonstrate that numerous patients still had articulation problems. The speech was analysed by plastic surgeons and although I am fully aware that some surgeons are able in doing this, for future studies I would suggest that the speech and articulation should be analysed by speech- and language pathologists.

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An online course improves nurses' awareness of their role as antimicrobial stewards in nursing homes

Publication date: Available online 8 February 2017
Source:American Journal of Infection Control
Author(s): Brigid M. Wilson, Sue Shick, Rebecca R. Carter, Barbara Heath, Patricia A. Higgins, Basia Sychla, Danielle M. Olds, Robin L.P. Jump
BackgroundTo support the role of nurses as active proponents of antimicrobial stewardship in long-term care facilities, we developed an educational intervention consisting of a free online course comprised of 6 interactive modules. Here, we report the effect of the course on the knowledge, beliefs, and attitudes toward antimicrobial stewardship of nurses working in long-term care facilities.MethodsWe used a paired pre- and postcourse survey instrument to assess nurses' knowledge regarding the care of long-term care facility residents with infections and attitudes and beliefs regarding antimicrobial stewardship.ResultsThere were 103 respondents, registered nurses or licensed practical nurses, who completed the pre- and postsurveys. Their mean knowledge scores improved from 75% (precourse) to 86% (postcourse, P < .001). After the course, nurses' agreement that their role influences whether residents receive antimicrobials increased significantly (P < .001).ConclusionsThe online course improves nurses' knowledge regarding the care of long-term care facility residents with infections and improves their confidence to engage in antimicrobial stewardship activities. Empowering nurses to be antimicrobial stewards may help reduce unnecessary antibiotic use among institutionalized older adults.



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Outcome of strict implementation of infection prevention control measures during an outbreak of Middle East respiratory syndrome

Publication date: Available online 8 February 2017
Source:American Journal of Infection Control
Author(s): Hassan E. El Bushra, Hussain A. Al Arbash, Mutaz Mohammed, Osman Abdalla, Mohamed N. Abdallah, Zayid K. Al-Mayahi, Abdallah M. Assiri, Abdulaziz A. BinSaeed
BackgroundThe objective of this retrospective cohort study was to assess the impact of implementation of different levels of infection prevention and control (IPC) measures during an outbreak of Middle East respiratory syndrome (MERS) in a large tertiary hospital in Saudi Arabia. The setting was an emergency room (ER) in a large tertiary hospital and included primary and secondary MERS patients.MethodsRapid response teams conducted repeated assessments of IPC and monitored implementation of corrective measures using a detailed structured checklist. We ascertained the epidemiologic link between patients and calculated the secondary attack rate per 10,000 patients visiting the ER (SAR/10,000) in 3 phases of the outbreak.ResultsIn phase I, 6 primary cases gave rise to 48 secondary cases over 4 generations, including a case that resulted in 9 cases in the first generation of secondary cases and 21 cases over a chain of 4 generations. During the second and third phases, the number of secondary cases sharply dropped to 18 cases and 1 case, respectively, from a comparable number of primary cases. The SAR/10,000 dropped from 75 (95% confidence interval [CI], 55-99) in phase I to 29 (95% CI, 17-46) and 3 (95% CI, 0-17) in phases II and III, respectively.ConclusionsThe study demonstrated salient evidence that proper institution of IPC measures during management of an outbreak of MERS could remarkably change the course of the outbreak.



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Perioperative participation of orthopedic patients and surgical staff in a nasal decolonization intervention to reduce Staphylococcus spp surgical site infections

Publication date: Available online 8 February 2017
Source:American Journal of Infection Control
Author(s): Anildaliz Mullen, Helen J. Wieland, Eric S. Wieser, Ernst W. Spannhake, Rebecca S. Marinos
With the goal of reducing rates of surgical site infections in our spine patients, we initiated a trial to investigate the impact of adding perisurgical nasal decolonization involving patients and surgical and nursing staff. We combined immediate presurgical application of a nonantibiotic alcohol-based nasal antiseptic with existing chlorhexidine bath or wipes in a comprehensive pre- and postoperative decolonization protocol. Mean infection rates were significantly decreased by 81% from 1.76 to 0.33 per 100 surgeries during the 15-month trial, when compared with the prior 9-month baseline.



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Barriers, perceptions, and adherence: Hand hygiene in the operating room and endoscopy suite

Publication date: Available online 8 February 2017
Source:American Journal of Infection Control
Author(s): Laura Pedersen, Kimberly Elgin, Barbara Peace, Nadia Masroor, Michelle Doll, Kakotan Sanogo, Wilhelm Zuelzer, Gene Peterson, Michael P. Stevens, Gonzalo Bearman
We examined the perceptions and barriers to nonsurgical scrubbed hand hygiene in the operating room and endoscopy procedure room using 2 anonymous Likert-scale surveys. Results indicated poor role modeling, inconvenience, and the need to monitor hand hygiene and feedback data to providers because of poor self-awareness of hand hygiene practices.



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Pseudo-outbreak of Penicillium in an outpatient obstetrics and gynecology clinic

Publication date: Available online 8 February 2017
Source:American Journal of Infection Control
Author(s): Geetika Sood, Kerri Huber, Lisa Dam, Stefan Riedel, Lisa Grubb, Jonathan Zenilman, Trish M. Perl, Cynthia Argani
We report an unusual pseudo-outbreak of Penicillium that occurred in patients seen in an outpatient obstetrics and gynecology clinic. The pseudo-outbreak was detected in late 2012, when the microbiology department reported a series of vaginal cultures positive for Penicillium spp. Our investigation found Penicillium spp in both patient and environmental samples and was potentially associated with the practice of wetting gloves with tap water by a health care worker prior to patient examination.



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Distribution of Endomorphin-like-immunoreactive neurones in the brain of the cichlid fish Oreochromis mossambicus

Abstract

Endomorphins are tetrapeptides involved in pain and neuroendocrine responses with high affinity for mu opioid receptors in mammals. In the present investigation, we studied the distribution of endomorphin-like-immunoreactive (EM-L-ir) neurones in the brain of the cichlid fish Oreochromis mossambicus. Application of antisera against endomorphin 1 and 2 (EM-1-2) revealed the presence of EM-L-ir somata and fibres throughout the different subdivisions of the olfactory bulb such as the olfactory nerve layer and the granule cell layer. While the extensions of EM-L-ir fibres were seen along the medial olfactory tract, intensely labeled EM-L-ir somata were found in different subdivisions of the telencephalon. In the diencephalon, intensely stained EM-L-ir neurones were noticed in the preoptic area, the nucleus preopticus pars magnocellularis, the suprachiasmatic nucleus, the nucleus lateralis tuberis pars lateralis (NLTl) and the nucleus lateralis tuberis pars medialis (NLTm) regions, whereas projections of EM-L-ir fibres were also seen along the hypothalamo-hypophyseal tract suggested a possible hypophysiotrophic role for these neurones. Intense to moderately stained EM-L-ir neurones were noticed in different subdivisions of thalamic nucleus such as the dorsal posterior thalamic nucleus, commissura posterior, ventromedial thalamic nucleus, nucleus posterior tuberis, ventrolateral thalamic nucleus and medial preglomerular nucleus. Numerous intensely stained perikarya and axonal fibres were also noticed throughout the inferior lobe, along the periventricular margin of the reccessus lateralis, and in the nucleus recesus lateralis regions. In addition, numerous moderately labeled EM-like neuronal populations were found in the secondary gustatory nucleus and rostral spinal cord. The widespread distribution of EM-L-ir neurones throughout the brain and spinal cord indicate diverse roles for these cells in neuroendocrine and neuromodulatory responses for the first time in fish. The study provides further insight into the possible existence of EM-like peptides in early vertebrate lines and suggests that these peptides might have been well-conserved during the course of evolution.

This article is protected by copyright. All rights reserved.

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Improving Nutrition Students’ Knowledge and Perceived Competence to Provide Nutrition Education to Adults with Disabilities via Experiential Learning

Publication date: Available online 7 February 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Sandra Baker, Jillian Trabulsi, Taylor Evans, Elizabeth Smith




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A Semi-Quantitative Food Frequency Questionnaire Validated in Hispanic Infants and Toddlers Aged 0 to 24 Months

Publication date: Available online 7 February 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Cristina Palacios, Sona Rivas-Tumanyan, Eduardo J. Santiago-Rodríguez, Olga Sinigaglia, Elaine M. Ríos, Maribel Campos, Beatriz Diaz, Walter Willett
BackgroundThere are limited validated food frequency questionnaires (FFQs) for infants and toddlers, most of which were evaluated in Europe or Oceania, and the ones available for use in the United States have important limitations.ObjectiveOur aim was to assess the validity of an FFQ developed for infants and toddlers.DesignA semi-quantitative FFQ was developed that included 52 food items, their sources, and portion sizes. The FFQ inquired about diets over the previous 7 days. Its validity was assessed in a cross-sectional study. Participants completed the FFQ, followed by a 24-hour recall on two occasions with 1 week between data collection.Participants/settingA total of 296 caregivers of infants and toddlers aged 0 to 24 months enrolled in the Special Supplemental Nutrition Program for Women, Infants, and Children, Puerto Rico.Main outcome measuresIntake of nutrients and food groups were averaged for the two FFQs and the two 24-hour food recalls, and adjusted for energy intake.Statistical analyses performedSpearman correlations were performed for intakes of energy, nutrients, and foods between administrations and between instruments. Correlation coefficients were de-attenuated to account for variation in the 24-hour recalls.ResultsA total of 241 participants completed the study. Intake of all nutrients and foods were significantly correlated between FFQs and 24-hour recalls and between the means of FFQs and 24-hour food recalls. The de-attenuated correlation for nutrients between the FFQs and 24-hour recalls ranged from 0.26 (folate) to 0.77 (energy), with a mean correlation of 0.53. The de-attenuated correlation for food groups between the FFQs and 24-hour recalls ranged from 0.28 (sweets) to 0.80 (breast milk), with a mean correlation of 0.55. When analyses were restricted to those consuming foods other than breast milk or formula (n=186), results were similar.ConclusionsThis semi-quantitative FFQ is a tool that offers reasonably valid rankings for intake of energy, nutrients, foods, and food groups in this sample of infants and toddlers.



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Cognitive and behavioral therapies in the treatment of insomnia: a meta-analysis

Insomnia is a major public health problem considering its high prevalence, impact on daily life, co-morbidity with other disorders and societal costs. Cognitive behavioral treatment for insomnia (CBTI) is currently considered to be the preferred treatment. However, no meta-analysis exists of all studies using at least one component of CBTI for insomnia, which also uses modern techniques to pool data and to analyze subgroups of patients. We included 87 randomized controlled trials, comparing 118 treatments (3724 patients) to non-treated controls (2579 patients).

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A Preterm Newborn in “the Barrel Syndrome”

Publication date: Available online 8 February 2017
Source:Pediatric Neurology
Author(s): Bárbara Muñoz Amat, Sara Vázquez Román, Carmen Gallego Herrero, Noemí Núñez-Enamorado, Óscar Toldos González, Carmen R. Pallás Alonso




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Growth and psychological development in post-operative patients of anterior encephaloceles

Publication date: Available online 8 February 2017
Source:Pediatric Neurology
Author(s): Hemonta K. Dutta, C. Wachana Khangkeo, Kaberi Baruah, Debasish Borbora
PurposeAnterior encephaloceles are rare malformations frequently associated with other brain anomalies. This study evaluates the growth and psychological development of children following encephalocele repair.Materials & methodsGrowth and psychological assessment was done in 24 children with only encephalocele (group-I), 9 children with encephalocele and hydrocephalus (group-II), 7 children with encephalocele, hydrocephalus and secondary malformations (group-III) and 40 apparently healthy controls. Psychological assessment was done by evaluating intelligence and temperament.ResultsSingle-stage repair was performed in 38 children, 2 underwent multistage repair. Major post-operative complications were noted in 3 patients. The follow-up period ranged from 12 to 168 months, during which the growth velocity declined significantly among group-II and group-III patients when compared to controls. After age-adjusting body mass index (BMI), our data revealed that group-III participants had a significantly (p=0.02) lower BMI than the control group. Group III also had poor indices for intelligence quotient (IQ) (p≤0.01) and temperament (p≤0.01). Female patients had lower temperament indices as compared to unaffected females- approach withdrawal (p≤0.01), mood (p=0.026) and intensity (p=0.03). Overall, increased disease severity adversely affected psychological indices.ConclusionAnterior encephalocele patients without associated intracranial defects had excellent post-operative outcomes in terms of growth and psychological developments. Hydrocephalus and agenesis of corpus callosum had least impact on the psychological development. However the presence of secondary brain defects led to developmental delays. Gender differences in temperament explains the need for distinct treatment regimen to assess psychosocial well-being for male and female cases.



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Outcomes of diagnostic exome sequencing in patients with diagnosed or suspected autism spectrum disorders

Publication date: Available online 8 February 2017
Source:Pediatric Neurology
Author(s): Mari Rossi, Dima El-Khechen, Mary Helen Black, Kelly Farwell Hagman, Sha Tang, Zoe Powis
BackgroundExome Sequencing has recently proven to be a successful diagnostic method for complex neurodevelopmental disorders. However, the diagnostic yield of exome sequencing for autism spectrum disorders has not been extensively evaluated in large cohorts to date.Materials and MethodsWe performed diagnostic exome sequencing in a cohort of 163 individuals with autism spectrum disorder (ASD; 66.3%) or autistic features (33.7%).ResultsThe diagnostic yield observed in patients in our cohort was 25.8% (42/163) for positive/likely positive findings in characterized disease genes, while a candidate genetic etiology was reported for an additional 3.3% (4/120) of patients. Among the positive findings in the patients with ASD or autistic features, 61.9% were the result of de novo mutations. Patients presenting with psychiatric conditions or ataxia and/or paraplegia in addition to ASD or autistic features were significantly more likely to receive positive results compared to patients without these clinical features (95.6% vs. 27.1%, p <0.0001 83.3% vs. 21.2%, p <0.0001respectively). The majority of the positive findings were in recently identified ASD genes, supporting the importance of diagnostic exome sequencing for patients with ASD or autistic features as the causative genes might evade traditional sequential or panel testing.ConclusionsThese results suggest that diagnostic exome sequencing would be an efficient primary diagnostic method for patients with ASDs or autistic features. Moreover, our data may aid clinicians to better determine which subset of patients with ASD with additional clinical features would benefit the most from diagnostic exome sequencing.



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Editorial Board and Masthead

Publication date: February 2017
Source:Pediatric Neurology, Volume 67





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Early-Onset Parkinsonism: Case Report and Review of the Literature

Publication date: February 2017
Source:Pediatric Neurology, Volume 67
Author(s): Ahmed Al-Rumayyan, Christine Klein, Majid Alfadhel
BackgroundEarly-onset parkinsonism can be caused by PTEN-induced putative kinase 1 (PINK1) gene defects and is usually characterized by an age of onset in the fourth decade of life, slow disease progression, resting tremor, rigidity, bradykinesia, postural instability, and levodopa-induced dyskinesia.MethodsWe evaluated a child with early-onset symptoms and performed a literature review for previously reported examples of children aged 18 years or less with PINK1 gene defects.ResultsWe describe a five-year-old boy with autosomal recessive early-onset parkinsonism caused by a homozygous missense mutation in the PINK1 gene. This is the youngest individual yet reported with early-onset parkinsonism.ConclusionPINK1-type of early-onset parkinsonism can occur in very young patients, and phenotypic expression of PINK1 mutations may depend on age of onset and ethnicity.



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Table of Contents

Publication date: February 2017
Source:Pediatric Neurology, Volume 67





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Meetings of Interest

Publication date: February 2017
Source:Pediatric Neurology, Volume 67





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Thyroid High-Impact Articles

FREE ACCESS through February 20, 2017.
Read now:

Latest Impact Factor: 3.784
The Official Journal of: American Thyroid Association

Anti-Thyrotropin Autoantibodies in Patients with Macro-Thyrotropin and Long-Term Changes in Macro-Thyrotropin and Serum Thyrotropin Levels
Naoki Hattori, Takashi Ishihara, Naoki Matsuoka, Takanori Saito, Akira Shimatsu

No Effect of the Thr92Ala Polymorphism of Deiodinase-2 on Thyroid Hormone Parameters, Health-Related Quality of Life, and Cognitive Functioning in a Large Population-Based Cohort Study
Hanneke J.C.M. Wouters, Hannah C.M. van Loon, Melanie M. van der Klauw, Martin F. Elderson, Sandra N. Slagter, Anneke Muller Kobold, Ido P. Kema, Thera P. Links, Jana V. van Vliet-Ostaptchouk, Bruce H.R. Wolffenbuttel

Practical Performance of the 2015 American Thyroid Association Guidelines for Predicting Tumor Recurrence in Patients with Papillary Thyroid Cancer in South Korea
Seul Gi Lee, Woo Kyung Lee, Hye Sun Lee, Jieun Moon, Cho Rok Lee, Sang Wook Kang, Jong Ju Jeong, Kee-Hyun Nam, Woong Youn Chung, Young Suk Jo, Jandee Lee

Fusion Oncogenes Are the Main Genetic Events Found in Sporadic Papillary Thyroid Carcinomas from Children
Maria Isabel C. Vieira Cordioli, Lais Moraes, André U. Bastos, Paloma Besson, Maria Teresa de Seixas Alves, Rosana Delcelo, Osmar Monte, Carlos Longui, Adriano Namo Cury, Janete M. Cerutti

Single Point Mutations in Pediatric Differentiated Thyroid Cancer
Ali S. Alzahrani, Avaniyapuram Kannan Murugan, Ebtesam Qasem, Meshael Alswailem, Hindi Al-Hindi, Yufei Shi

Distribution of RET Mutations in Multiple Endocrine Neoplasia 2 in Denmark 1994-2014: A Nationwide Study
Jes Sloth Mathiesen, Jens Peter Kroustrup, Peter Vestergaard, Kirstine Stochholm, Per Løgstrup Poulsen, Åse Krogh Rasmussen, Ulla Feldt-Rasmussen, Mette Gaustadnes, Torben Falck Ørntoft, Thomas van Overeem Hansen, Finn Cilius Nielsen, Kim Brixen, Christian Godballe, Anja Lisbeth Frederiksen

 

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Correlation of Tumor and Peritumoral Edema Volumes with Survival in Patients with Cerebral Metastases

Background: Surgical resection in combination with radiotherapy in selected cases remains the best option for patients with cerebral metastases. Postoperative relapse of brain metastases occurs frequently and can be reduced by postoperative whole-brain radiotherapy (WBRT). Continuous spread of tumor cells from the primary lesions is debated as a cause of recurrence. It is well known that in gliomas, infiltration takes place within the surrounding edema. Obviously, most brain metastases are usually associated with peritumoral edema, which may act as an indicator of infiltration and more aggressive tumor biology. Therefore, we aimed to investigate the correlation of tumor and edema volumes with overall survival in patients with cerebral metastases. Patients and Methods: A total of 143 patients diagnosed with brain metastasis (male:female=1.1:1) who underwent surgical resection were included retrospectively in this analysis. Clinical data were retrieved from electronic patient files. The volumes of tumor and edema calculated by manual delineation. The ratio of edema to tumor volume was calculated, leading to dichotomization of the patients. Results: The median tumor volume was 20.1 cc (range=0.8-90.8 cc) and the median volume of edema 49.5 cc (range=0-179.9 cc). The volume of metastases did not significantly correlate with overall survival. The ratio of edema to tumor volume was also not a prognostic factor in terms of overall survival. Only surgical resection, preoperative recursive partitioning analysis class, and postoperative addition of WBRT, as well as female sex, demonstrated beneficial effects. Conclusion: The extent of edema surrounding cerebral metastases does not appear to influence overall survival in patients suffering from brain metastases, although it seems to be responsible for most of the patients' symptoms. The hypothesis that the extent of edema was disadvantageous concerning survival was supported by our data.

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De Novo Renal Cell Carcinoma of Native Kidneys in Renal Transplant Recipients: A Single-center Experience

Background: The risk of renal cell carcinoma (RCC) development in renal transplant recipients is 15-100 times higher than in the general population. The majority of RCCs found in renal transplant recipients develop in the recipient's native kidneys, only 9% of tumors develop in the allograft itself. The mechanisms of development of RCC in native kidneys and renal allografts are not completely understood. We present our experience in renal transplant recipients with RCC of native kidneys providing valuable and clinically applicable treatment and follow-up data. Patients and Methods: The records of 2,173 patients who underwent renal transplantation in our Department between March 1983 and December 2015 were retrospectively reviewed. Using these data, we analyzed the incidence and types of post-transplant RCCs, as well as their clinical courses, focusing on native malignancies. Results: We found 11 RCCs (0.5%) during the observation period in native kidneys. The mean (±SD) follow-up period was 50.54±32.80 months. Four patients died during this period (36.4%). Conclusion: Most RCCs in renal transplant recipients are low-stage, low-grade tumors with a favorable prognosis. Their diagnosis is usually incidental. RCC development in the native kidney of renal transplant recipients is an early event, frequently observed within 4 to 5 years after transplantation. The different natural history of these tumors is still undefined. Further research is needed to determine whether these differences are due to particular molecular pathways or to biases in relation to the mode of diagnosis.

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The Evolving Role of Local Treatments for HCC in the Third Millennium

Background: Hepatocellular carcinoma (HCC) represents the fifth most common malignancy and the third cancer-related cause of death worldwide. The aim of this review was to clarify the role of local treatments for HCC, analyzing the indications and defining future perspectives. Materials and Methods: A systematic literature search was performed independently by two of the authors according to the PRISMA statement guidelines. The search was limited to studies reported in English between January 2005 and June 2016. Results: The literature search yielded 238 articles; after duplicates were removed, 179 titles and abstracts were reviewed. Most relevant data and articles about radiofrequency ablation, transarterial chemoembolization, percutaneous ethanol injection, microwave ablation and radioembolization are reported and discussed. Conclusion: Data in the literature are confusing and difficult to compare due to the lack of prospective studies. Multidisciplinary and tailored approaches for each patient are key features, considering both guideline indications and patient-specific characteristics, and enhance hospital-specific best practice.

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Efficacy and Toxicity of Induction Therapy with Cladribine, Idarubicin, and Cytarabine (IAC) for Acute Myeloid Leukemia

We report our single-center experience with cytarabine and idarubicin for induction therapy for acute myeloid leukemia (AML) with an additional 5 days of cladribine (IAC therapy). From July 2012 to September 2014, 38 patients completed a full course of IAC induction. Median patient age was 61 years, 61% of patients were ≥60 years old, and 71% were male. The complete remission (CR) rate was 63% following a single induction course, three patients (8%) required a second induction course to achieve CR, for an overall response rate of 71%. The median duration of severe neutropenia was 30.5 days. Thirty-two percent of patients developed mucositis, 76% experienced diarrhea, and 61% developed a rash. Incidence of CR following IAC induction therapy for AML was comparable to historical data, but with frequent diarrhea, rash, and fungal infections. This study found IAC efficacy and toxicity was similar irrespective of age.

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Potential Predictive Role of MicroRNAs in the Neoadjuvant Treatment of Esophageal Cancer

Esophageal cancer is a disease with disappointing prognosis. Currently, there are no predictive factors that can identify patients who on the one hand would likely benefit from tri-modality management and, on the other hand, would not be significantly affected by the morbidity accompanying the treatment. MicroRNAs are short non-coding RNAs responsible for post-transcriptional modification of gene expression by binding to 3'-UTR of messenger RNA and represent emerging potential predictive biomarkers of treatment (chemotherapy and radiotherapy) efficacy and toxicity. We reviewed the current literature, addressing the potential predictive role of microRNAs for efficacy of chemotherapy (specifically cisplatin, 5-fluorouracil, doxorubicin and paclitaxel) and radiotherapy, including predicted targets in the cell. Altogether 82 articles were identified and included in this review. This may be the first review on this topic specifically focusing on neoadjuvant treatment of esophageal cancer.

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Mono- and Bi-weekly Hypofractionated Radiation Therapy for the Treatment of Epithelial Skin Cancer in Very Elderly Patients

Background/Aim: Epithelial skin cancer frequently occurs in the elderly population, sometimes in an advanced stage, when intensive treatments are needed. Radiotherapy can achieve high response rates. We evaluated efficacy and tolerability of hypofractionated radiotherapy in a population of very elderly patients with locally advanced epithelial skin cancer. Patients and Methods: Two different hypofractionated schedules were administered (21 patients): 6 Gy in 10 bi-weekly fractions (13 lesions) and 5 Gy in 12 bi-weekly fractions (13 lesions). Median age at treatment was 88 years, life expectancy was ≤5 years in 90.5%. Results: The overall response rate was 96.1%, with 92.4% complete responses. All patients experienced an improvement of their symptoms and a reduction of pain and medication. The median overall survival time was 28 months (95% confidence interval=4.7-51.2 months). At the time of analysis, 52.3% of patients had died. Conclusion: Hypofractionated radiotherapy is an effective option of treatment, with low toxicity and optimal results, and can also be safely administered to these frail patients.

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Italian Prostate Biopsies Group: 2016 Updated Guidelines Insights

Aim: To present a summary of the updated guidelines of the Italian Prostate Biopsies Group following the best recent evidence of the literature. Materials and Methods: A systematic review of the new data emerging from 2012-2015 was performed by a panel of 14 selected Italian experts in urology, pathology and radiology. The experts collected articles published in the English-language literature by performing a search using Medline, EMBASE and the Cochrane Library database. The articles were evaluated using a systematic weighting and grading of the level of the evidence according to the Grading of Recommendations Assessment, Development and Evaluation framework system. Results: An initial prostate biopsy is strongly recommended when i) prostate specific antigen (PSA) >10 ng/ml, ii) digital rectal examination is abnormal, iii) multiparametric magnetic resonance imaging (mpMRI) has a Prostate Imaging Reporting and Data System (PIRADS) ≥4, even if it is not recommended. The use of mpMRI is strongly recommended only in patients with previous negative biopsy. At least 12 cores should be taken in each patient plus targeted (fusion or cognitive) biopsies of suspicious area (at mpMRI or transrectal ultrasound). Saturation biopsies are optional in all settings. The optimal strategy for reducing infection complications is still a controversial topic and the instruments to reduce them are actually weak. The adoption of Gleason grade groups in adjunction to the Gleason score when reporting prostate biopsy results is advisable. Conclusion: These updated guidelines and recommendations are intended to assist physicians and patients in the decision-making regarding when and how to perform a prostatic biopsy.

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Carboplatin plus Weekly Paclitaxel Combined with Bevacizumab as First-line Treatment for Non-small Cell Lung Cancer

Aim: We aimed to evaluate the efficacy and safety of carboplatin plus weekly paclitaxel with bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC). Patients and Methods: Patients with stage IIIB/IV or postoperative recurrent NSCLC (n=33) were treated with carboplatin (area under the curve of 6) on day 1; paclitaxel (80 mg/m²) on days 1, 8, and 15; and bevacizumab (15 mg/kg) on day 1 repeated every 4 weeks, for four to six cycles; followed by maintenance bevacizumab (15 mg/kg) every 3 weeks. Results: The overall response rate was 76%. The median progression-free survival and overall survival were 8.4 months and 22.2 months, respectively. Grade 3-4 toxicities included neutropenia in 55% of patients, anemia in 18%, febrile neutropenia in 12%, and anorexia in 9%. No treatment-related deaths were observed. Conclusion: Carboplatin plus weekly paclitaxel with bevacizumab was effective and well tolerated by patients with advanced NSCLC.

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Possible Therapeutic Effects of Ozone Mixture on Hypoxia in Tumor Development

Recent literature highlights that ozone therapy could be considered a viable adjuvant therapy in oncological patients receiving radio-chemotherapy. The use of ozone therapy in these patients enhances the action of chemotherapy and at the same time reduces side-effects, such as nausea, vomiting, opportunistic infections, buccal ulcers, hair loss and fatigue. Such positive therapeutic effects of ozone therapy can cause a larger physical and mental wellbeing resulting in improved quality of life. This work reviews the recent acquisition of scientific knowledge regarding the ozone therapy and highlights the molecular and cellular pathways involved.

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The Preoperative Controlling Nutritional Status Score Predicts Survival After Curative Surgery in Patients with Pathological Stage I Non-small Cell Lung Cancer

Background: The prognostic Controlling Nutritional Status (CONUT) score is used to evaluate immuno-nutritional conditions and is a predictive factor of postoperative survival in patients with digestive tract cancer. We retrospectively analyzed clinicopathological features of patients with pathological stage I non-small cell lung cancer (NSCLC) to identify predictors or prognostic factors of postoperative survival and to investigate the role of preoperative CONUT score in predicting survival. Patients and Methods: We selected 138 consecutive patients with pathological stage I NSCLC treated from August 2005 to August 2010. We measured their preoperative CONUT score in uni- and multivariate Cox regression analyses of postoperative survival. Results: A high CONUT score was positively associated with preoperative serum carcinoembryonic antigen level (p=0.0100) and postoperative recurrence (p=0.0767). In multivariate analysis, the preoperative CONUT score [relative risk (RR)=6.058; 95% confidence interval (CI)=1.068-113.941; p=0.0407), increasing age (RR=7.858; 95% CI=2.034–36.185; p=0.0029), and pleural invasion (RR=36.615; 95% CI=5.900-362.620; p<0.0001) were independent prognostic factors. In Kaplan–Meier analysis of recurrence-free survival (RFS), cancer-specific survival (CS), and overall survival (OS), the group with high CONUT score had a significantly shorter RFS, CS, and OS than did the low-CONUT score group by log-rank test (p=0.0458, p=0.0104 and p=0.0096, respectively). Conclusion: The preoperative CONUT score is both a predictive and prognostic factor in patients with pathological stage I NSCLC. This immuno-nutritional score can indicate patients at high risk of postoperative recurrence and death.

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Aurora B Inhibitor TAK-901 Synergizes with BCL-xL Inhibition by Inducing Active BAX in Cancer Cells

Background: Aurora B kinase plays an essential role in chromosome segregation and cytokinesis, and is dysregulated in many cancer types, making it an attractive therapeutic target. TAK-901 is a potent aurora B inhibitor that showed efficacy in both in vitro and in vivo oncology models. Materials and Methods: We conducted a synthetic lethal siRNA screening to identify the genes that, when silenced, can potentiate the cell growth-inhibitory effect of TAK-901. Results: B-cell lymphoma-extra large (BCL-xL) depletion by siRNA or chemical inhibition synergized with TAK-901 in cancer cell lines. As a mechanism of synthetic lethality, active BCL2 associated X, apoptosis regulator (BAX) was induced by TAK-901. BCL-xL protected cells from BAX-dependent apoptosis induction. Therefore, TAK-901 sensitizes cancer cells to BCL-xL inhibition. Conclusion: Polyploid cells induced by TAK-901 are vulnerable to BCL-xL inhibition. Our findings may have an impact on combination strategies with aurora B inhibitors in clinical studies.

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Liver Metastasis of Urothelial Carcinoma with Hepatoid Features: An Unusual Morphological Finding

Bladder cancer comprises of many well-known variants and divergent histologies, both of urothelial and adenocarcinomatous type. Extrahepatic tumors with features that resemble hepatocellular carcinoma, often referred to as hepatoid adenocarcinomas, have been described in many different organs, and are aggressive and prognostically unfavorable. Hepatoid features of bladder cancer are unusual and rarely reported. We report a unique case of a metastatic lesion to the liver consisting of a urothelial carcinoma with hepatoid features, a tumor that likely falls within the hepatoid adenocarcinoma spectrum. It is an unusual morphological finding in urothelial carcinoma and is important to recognize due to its potential for aggressive behavior, particularly when it involves a liver lesion in which hepatocellular carcinoma may be suspected.

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Salinomycin Abolished STAT3 and STAT1 Interactions and Reduced Telomerase Activity in Colorectal Cancer Cells

Background: Colorectal cancer is the third leading cause of cancer-related mortality in most developed countries. This mortality is mainly due to the metastatic progression to the liver with frequent recurrence. Colorectal cancer remains a therapeutic challenge and this has intensified the search for new drug targets. In an effort to establish a novel targeted-therapy, we studied the molecular mechanisms of cancer stem cell inhibitor salinomycin. Materials and Methods: Co-immunoprecipitation was performed to examine STAT3-STAT1 protein interactions. Telomerase activity was measured by polymerase chain reaction (PCR) and ELISA assays. Apoptosis and cell stress arrays were analyzed to identify key proteins responding to salinomycin treatments. Results: IL-6 and TNF-α induced STAT3 and STAT1 interactions, however the interactions were abolished by salinomycin challenge. Salinomycin reduced cancer stem cell phenotype and decreased telomerase activity of colorectal cancer cells. Conclusion: Our work uncovers a new mechanism through which salinomycin inhibits cancer stemness suggesting a novel targeted-therapy for metastatic colorectal cancer.

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Cytogenetic Biomonitoring in Buccal Mucosal Cells from Municipal Solid Waste Collectors

Waste collectors collect, transport, and process the garbage produced by people living in the city. Nowadays, this activity requires special attention due to the environmental impact of garbage and its potential consequences on human health. The aim of this study was to evaluate potential cytotoxic and mutagenic effects of garbage collection on waste collectors. For this purpose, a total of 47 male waste collectors aged from 24 to 53 years were included in the experimental group. A total of 30 men matched by age were used as the control group. Cytotoxicity and mutagenicity were analyzed by micronucleus test in buccal mucosaI cells. No statistically significant difference (p>0.05) in the frequency of micronuclei was detected in the waste collectors when compared to controls. Nevertheless, higher frequencies of karyolysis and pyknosis (p<0.05) were detected in buccal mucosaI cells from waste collectors when compared to matched controls. Taken together, our results indicate that waste collectors comprise an at-risk group as a result of increased cytotoxicity apparent from buccal mucosa cells.

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Fumonisin B1 Inhibits Endoplasmic Reticulum Stress Associated-apoptosis After FoscanPDT Combined with C6-Pyridinium Ceramide or Fenretinide

Background/Aim: Combining an anticancer agent fenretinide (HPR) or C6-pyridinium ceramide (LCL29) with Foscan-mediated photodynamic therapy (FoscanPDT) is expected to augment anticancer benefits of each substance. We showed that treatment with FoscanPDT+HPR enhanced accumulation of C16-dihydroceramide, and that fumonisin B1 (FB), an inhibitor of ceramide synthase, counteracted caspase-3 activation and colony-forming ability of head and neck squamous cell carcinoma (HNSCC) cells. Because cancer cells appear to be more susceptible to increased levels of the endoplasmic reticulum (ER) stress than normal cells, herein we tested the hypothesis that FoscanPDT combined with HPR or LCL29 induces FB-sensitive ER stress-associated apoptosis that affects cell survival. Materials and Methods: Using an HNSCC cell line, we determined: cell survival by clonogenic assay, caspase-3 activity by spectrofluorometry, the expression of the ER markers BiP and CHOP by quantitative real-time polymerase chain reaction and western immunoblotting, and sphingolipid levels by mass spectrometry. Results: Similar to HPR+FoscanPDT, LCL29+FoscanPDT induced enhanced loss of clonogenicity and caspase-3 activation, that were both inhibited by FB. Our additional pharmacological evidence showed that the enhanced loss of clonogenicity after the combined treatments was singlet oxygen-, ER stress- and apoptosis-dependent. The combined treatments induced enhanced, FB-sensitive, up-regulation of BiP and CHOP, as well as enhanced accumulation of sphingolipids. Conclusion: Our data suggest that enhanced clonogenic cell killing after the combined treatments is dependent on oxidative- and ER-stress, apoptosis, and FB-sensitive sphingolipid production, and should help develop more effective mechanism-based therapeutic strategies.

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Does Rectus Sheath Block Analgesia Alter Levels of the Oxidative Stress Biomarker Glutathione Peroxidase: A Randomised Trial of Patients with Cancer and Benign Disease

Aim: To evaluate whether the overall satisfaction, as measured by numeric rating scale (NRS), regarding rectus sheath block (RSB) analgesia is associated with the plasma glutathione peroxidase (GPX1) level. The second end-point of the study was to evaluate the differences in GPX1 levels in patients with and without RSB analgesia, with special emphasis on benign or malign disease status. Patients and Methods: Initially, 56 patients were randomized to the placebo group (n=12) and to one of three active RSB analgesia groups: single-dose (n=16), repeated-dose (n=12) and continuous infusion (n=16) groups. The plasma level of GPX1 was measured at three time points: just before, immediately after and 24 h after surgery. The overall satisfaction and an opinion on the success of the analgesic procedure were surveyed using an 11-point numeric rating scale 24 h postoperatively (NRS from 0, completely dissatisfied, to 10, fully satisfied). Results: The placebo group and the three active groups were similar in terms of their perioperative data. The plasma level of GPX1 decreased postoperatively in all four groups. No differences were detected in the GPX1 values between the placebo and the three active groups combined preoperatively and immediately after operation. However, the patients in the single-dose group had a significantly lower median GPX1 values 24 h after surgery compared to the three other groups separately (p=0.032). The median (interquartile range) plasma level of GPX1 differed significantly between patients with benign disease and those with cancer preoperatively (18.0, 12.5-22.0 versus 10.0, 6.3-18.8 pg/ml, p=0.006) and cancer diagnosis was correlated with lower individual plasma GPX1 values (r=–0.42, p=0.004). Conclusion: The placement of RSB analgesia does not significantly affect the level of oxidative stress biomarker GPX1 in patients with benign disease or cancer. A new finding with possible clinical relevance is that patients with cancer appeared to have a trend for lower plasma GPX1 values.

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Synergistic Inhibitory Effect of Traditional Chinese Medicine Astragaloside IV and Curcumin on Tumor Growth and Angiogenesis in an Orthotopic Nude-Mouse Model of Human Hepatocellular Carcinoma

Aim: The aim of the present study was to investigate the efficacy of the traditional Chinese medicine (TCM), astragaloside IV (AS-IV) and curcumin on tumor growth and angiogenesis in an orthotopic nude-mouse model of human hepatocellular carcinoma (HCC). We have previously shown the usefulness of orthotopic models of human cancer for evaluation of the efficacy of TCM. Materials and Methods: Nude mice with orthotopic HepG2 HCC were treated with vehicle control (0.01 ml/g normal saline), cisplatinum (2 mg/kg), AS-IV (20 mg/kg), curcumin (100 mg/kg) or AS-IV plus curcumin (20 mg/kg + 100 mg/kg). Tumor inhibition in each group was evaluated by tumor weight at autopsy. The effect of AS-IV and curcumin on tumor angiogenesis was assessed by CD34 staining and expression of fibroblast growth factor-2 (FGF2), matrix metalloproteinase 2 (MMP2), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), thrombosis-related factor tissue factor (TF) and coagulation factor VII (FVII), as well as microRNAs miR-122 and miR-221. Results: AS-IV and curcumin alone and in combination significantly reduced mean tumor weight compared to vehicle control (p<0.05). Tumor microvessel count was reduced by AS-IV and curcumin alone. Expression of FGF2, MMP2, VEGF, HGF, TF and FVII was reduced by AS-IV and curcumin alone. AS-IV and curcumin alone up-regulated expression of miR-122 and down-regulated that of miR-221. The combination of AS-IV and curcumin demonstrated significant synergistic effects on microvessel count as well as on expression of angiogenic and thrombosis-related factors and microRNAs. Conclusion: The present study indicates future clinical potential of combination therapy with AS-IV and curcumin for HCC.

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