Σάββατο 5 Μαΐου 2018
Scholar : Chinese Scientific Journal of Hearing and Speech Rehabilitation, Year 2018, Issue 01 -New Issue Alert.
Motivational interviewing for enhancing engagement in Intimate Partner Violence (IPV) treatment: A review of the literature
Publication date: Available online 4 May 2018
Source:Aggression and Violent Behavior
Author(s): Sara Soleymani, Eileen Britt, Mark Wallace-Bell
Client engagement is an essential component in Intimate Partner Violence (IPV) treatment. Engaged clients are more likely to engage with treatment and report a greater degree of treatment satisfaction. Likewise, enhanced engagement is associated with positive treatment outcomes such as session attendance and homework compliance. Only small effect sizes have been reported for reductions in IPV itself, and treatment engagement has been identified as an important factor in this, with studies reporting high rates of non-attendance and drop-out.This article reviews research on the efficacy of motivational interviewing (MI) as a pre-treatment intervention to promote treatment engagement for men who have been mandated or self-referred to attend Intimate Partner Violence treatment. Although limited in number (n = 5), these studies revealed a significant improvement in the level of engagement, session attendance and homework compliance following MI. Further research to focus on MI for treatment engagement, specifically, rather than MI for behaviour change is needed.
https://ift.tt/2Igcphz
A systematic review of the association between rape myth acceptance and male-on-female sexual violence
Publication date: Available online 4 May 2018
Source:Aggression and Violent Behavior
Author(s): Emma J. Yapp, Ethel Quayle
Rape myth acceptance is considered an established risk factor for male-on-female sexual violence, and is therefore the target of a number of primary prevention programmes. However, there is not a clear evidence base substantiating the role of rape myth acceptance in sexual violence, nor any reviews of recent literature. This review systematically searched relevant Psychology and Social Science databases in Autumn 2016, in order to collate cross-sectional and longitudinal research on the association between rape myth acceptance and self-reported sexual violence. The analysis established associations between these variables in all but one study (Warren, Swan, & Allen, 2015), and two longitudinal studies demonstrated that rape myth acceptance differentiates non-perpetrators from those who go on to exhibit sexual violence behaviours. These findings provide support for the targeting of rape myth acceptance in primary prevention strategies. However, a number of failings within this literature were also identified: instruments used to analyse rape myth acceptance were widely varied; the comprehensiveness of study reporting was universally flawed; measures were rarely taken to ensure participants were heterosexual men; and there remains a dearth of longitudinal evidence, as well as a lack of research outside of the United States. Future directions and other limitations are discussed.
https://ift.tt/2JWJnAM
Influence of psychological contract on workplace bullying
Publication date: Available online 4 May 2018
Source:Aggression and Violent Behavior
Author(s): M. Rajalakshmi, B. Naresh
A few decades back, organizations were very much targeted towards profit, productivity, performance and turnovers. But now some organizations are only concerned about their employee's well-being and satisfaction for better performance in their organization. In this esteem, researchers and organization are considering various factors which improve their employee satisfaction, employee well-being, employee productivity, employee morale, employee performance, employee behavior and attitude in the work environment. To increase this relationship between employee and employer, many scholars and management are focusing on various areas like, organizational justice, career satisfaction, employee Work Performance, employee and employer relationship in workplace, consequences of psychological contract, and effects of psychological contract on job outcomes and violation of psychological contract.Based on the many literature, there is a need for research on workplace bullying especially to know its impact is due to psychological contract violation in industries. Various researchers have undergone to know the behavior outcome of workplace bullying in other sectors like hospitality, service, IT Industry, etc. The purpose of this review research is to look at impact of psychological contract on workplace bullying among employees.
https://ift.tt/2IgbXzT
Hate speech review in the context of online social networks
Publication date: Available online 4 May 2018
Source:Aggression and Violent Behavior
Author(s): Naganna Chetty, Sreejith Alathur
Advances in Internet Technologies (ITs) and online social networks have made more benefits to humanity. At the same time, the dark side of this growth/benefit has led to increased hate speech and terrorism as most common and powerful threats globally. Hate speech is an offensive kind of communication mechanism that expresses an ideology of hate using stereotypes. Hate speech targets different protected characteristics such as gender, religion, race, and disability. Control of hate speech can be made using different national and international legal frameworks. Any intentional act directed against life or related entities causing a common danger is known as terrorism. There is a common practice of discussing or debating hate speech and terrorism separately. In the recent past, most of the research articles have discussed either hate speech or terrorism. Hate speech is a type of terrorism and follows an incident or trigger event of terrorism. Online social networks are the result of ITs and evolved rapidly through the popularity among youth. As both the activities are near to close and makes use of online social networks, the collective discussion is appropriate. Therefore we have a review on hate speech with different classes and terrorism with cyber use in the framework of online social networks. With the help of combined effort from the government, the Internet Service Providers (ISPs) and online social networks, the proper policies can be framed to counter both hate speech and terrorism efficiently and effectively.
https://ift.tt/2JZ8lj4
Consistency of gender differences in bullying in cross-cultural surveys
Publication date: Available online 2 May 2018
Source:Aggression and Violent Behavior
Author(s): Peter K. Smith, Leticia López-Castro, Susanne Robinson, Anke Görzig
Many studies have reported on gender differences in bully and victim rates, but with the majority of reports from a small number of countries. Here we report on such gender differences from five large cross-national data bases. We report on overall male:female (M:F) ratios, and variations in these by age (or grade), by survey time point, and by offline/online bullying. We also compare consistency of M:F ratios across countries, over the five surveys. The preponderance of male perpetrators of bullying is found consistently across surveys, and survey time point. It is also consistent by age, but HBSC data suggest a curvilinear trend in early adolescence. Males also tend to more frequently be victims of bullying, consistent across age and survey time point, but with variations by survey. There is some indication of a decrease in M:F ratio recently in mid-adolescence, possibly related to online bullying. At least relatively, females are more involved as victims of online than offline bullying. Comparing recent findings on M:F ratio across countries for the five surveys, correlations vary from high to near zero. Implications for the explanation of gender differences in different countries, the comparability of data from different surveys, and for gender-specific interventions, are discussed.
https://ift.tt/2IdlJ5I
Cyberhate: A review and content analysis of intervention strategies
Publication date: Available online 5 May 2018
Source:Aggression and Violent Behavior
Author(s): Catherine Blaya
This paper presents a review of intervention programmes against cyberhate. Over the last decade, the preoccupation over the use of electronic means of communication as a tool to convey hate, racist and xenophobic contents rose tremendously. NGOs, legal professionals, private companies, and civil society have developed interventions but little is known about their impact. For this review we followed the method and protocol from the guidelines from the Cochrane Collaboration Handbook for Systematic Reviews and the Campbell Collaboration Crime and Justice guidelines. The review identified three key intervention areas: law, technology and education through the empowerment of the individuals under the form of counter-speech. No specific intervention towards aggressors was found and most projects focus on prevention or victims through confidence building and skills learning to speak out, report and potentially react in an appropriate way. We did not find any rigorously assessed interventions, which highlights a gap in research and stresses the need for this type of studies. The evaluation of effectiveness of interventions needs to be included in the near future research agenda. Up to now, although intentions are good, we have no evidence that the steps that are undertaken are effective in preventing and reducing cyberhate.
https://ift.tt/2JUu6Ai
Sex differences in temperament: A partial explanation for the sex difference in the prevalence of serious antisocial behaviors
Source:Aggression and Violent Behavior, Volume 40
Author(s): Robert Eme
Although temperamental traits, which refer to biologically based early-developing behavioral and emotional tendencies, have long been understood to be important constructs for understanding normal and abnormal development, their relevance to criminal justice has only recently been recognized. This paper extended belated recognition to an examination of how the sex difference in three temperamental dimensions contributed to the massive sex difference in the severest forms of antisocial behavior. The dimensions were attention/regulation, activity level, and emotionality. A plausible biological mechanism influencing each of these sex differences was also discussed.
https://ift.tt/2rnxs82
The enduring effect of maltreatment on antisocial behavior: A meta-analysis of longitudinal studies
Source:Aggression and Violent Behavior, Volume 40
Author(s): Teresa Braga, Olga Cunha, Ângela Maia
The maltreatment-antisocial behavior relationship has been a focus of research for decades. Nevertheless, understanding this association has been largely based on cross-sectional designs and on juvenile antisocial outcomes. The present meta-analysis aimed to extend previous work on the maltreatment-antisocial relation by focusing on prospective longitudinal studies that have followed-up participants into adulthood. General, maltreatment and abusive intimate partner violent behaviors were included as outcomes. A total of 14 studies including 18 independent samples and 20,946 individuals were considered. Our results revealed that maltreated youth are nearly two times as likely to engage in antisocial behaviors in adulthood compared with their non-maltreated peers (OR = 1.96; CI[1.42, 2.71]). The relation between maltreatment and antisocial behavior was stronger when less covariates or the bivariate associations between them were considered, and maltreatment assessed in both childhood and adolescent years was more strongly related to the antisocial outcome. Nevertheless, the maltreatment-antisocial behavior link prevailed in the contrasting conditions, i.e., maltreatment assessed in childhood or in adolescent years, in multivariate analyses. Our results support an enduring effect of maltreatment on subsequent involvement in antisocial behavior, stressing the importance of preventing this victimization experience or, at best, the adverse consequences of maltreatment.
https://ift.tt/2JWIXdG
Sexual abuse and charismatic cults
Publication date: Available online 21 April 2018
Source:Aggression and Violent Behavior
Author(s): Hava Dayan
The article explores the enigmatic yet dire phenomenon of sexual abuse in cultic circumstances. Such a quest into the realm of cults is vital since, "sexual exploitation of women in cults of all types is widespread, and, to date, is possibly the least talked about, and certainly the least researched, aspect of cult life" (Lalich, 1997, pp. 7). Sexual abuse of consenting adults has been examined in circumstances of formal authority (workplace, mental institutions, jailing institutions and even academic institutions), however the study of consenting adults in informal circumstances of authority in general, and of cultic spiritual authority in particular, has hardly been addressed.The article attempts to do so, supported by empirical extrapolations from a recent criminal ruling of the Jerusalem District Court. Are women cult members genuinely capable of exercising their sexual autonomy with their charismatic cult leader? If they are unable to do so in cultic circumstances, does this impair their informed consent to the point of rendering their sexual relations with the cult leader legally abusive and criminal? The answers to these questions have dire consequences for both women cult members and cult leaders. Through a comprehensive review of the legal, criminological and sociological aspects of the case, the article sheds much needed light on one of the most enigmatic and elusive fields: sexual abuse of adults by a spiritual authority.
https://ift.tt/2rmVJLD
Structure, properties and interactions in ionomer/lignin blends
Publication date: 15 August 2018
Source:Materials & Design, Volume 152
Author(s): Gábor Szabó, Dávid Kun, Károly Renner, Béla Pukánszky
Blends were prepared from lignin and ionomers, i.e. ethylene-methacrylic acid copolymers partially neutralized with inorganic salts for the first time in order to check the possible effect of ionic bonds on the structure and properties of the blends. A low density polyethylene and an ethylene-acrylic acid copolymer without any neutralization were used as references. The lignin content of the blends varied between 0 and 60 vol%. The components were homogenized in an internal mixer and the blends were characterized by various methods including dynamic mechanical analysis, differential scanning calorimetry and tensile testing. The size of dispersed lignin particles was determined from scanning electron micrographs, and component interactions were estimated quantitatively. The properties of ionomer/lignin blends indicated the development of strong interactions between the components. The simultaneous action of hydrogen bonds of non-neutralized methacrylic acid moieties and ionic bonds resulted in the formation of small, dispersed lignin particles of the size of several tenth of a micron. Surprisingly, hydrogen bridges improve interactions and compatibility more than ionic bonds. Contrary to most blends prepared from other polymers, ionomer/lignin blends can be produced with a reasonable combination of properties at moderate lignin contents.
Graphical abstract
https://ift.tt/2HRsACG
A physically based constitutive model for predicting the surface integrity in machining of Waspaloy
Publication date: 15 August 2018
Source:Materials & Design, Volume 152
Author(s): Stano Imbrogno, Sergio Rinaldi, Domenico Umbrello, Luigino Filice, Rodolfo Franchi, Antonio Del Prete
During machining, surface modifications are directly related to the process dynamic affecting the thermo-mechanical properties of the materials. The physics phenomena (such as dynamic recrystallization, hardening and recovery effects) are difficult to be experimentally evaluated during the cutting operations, therefore the simulations are very important tools to understand their evolution. Orthogonal cutting experiments were conducted on Waspaloy under different cutting parameters and lubri-cooling conditions. The machined surfaces were evaluated via optical microscope and the surface integrity was analysed in terms of microstructural changes and microhardness. The deformation mechanisms that occurred in chip formation and on the machined surface were investigated in order to build-up a physically based constitutive model. Subsequently, the developed material model was implemented via sub-routine in a commercial Finite Element software. The numerical prediction strategy was validated through comparisons with experimental outcomes (cutting forces, temperature and metallurgical changes) and employed to predict the variables of scientific interest (microstructural modifications and microhardness). The overall absolute error in predicting the principal cutting force, feed force and temperature were approximately equal to 5%, 9% and 7% respectively. Furthermore, the developed model permits to explore the metallurgical changes and their evolution during the machining process varying cutting parameters and lubri-cooling conditions.
Graphical abstract
https://ift.tt/2rokd6h
Underlying Systemic Diseases in Pyoderma Gangrenosum: A Systematic Review and Meta-Analysis
Abstract
Background
There is little consensus regarding the prevalence and distribution of underlying systemic diseases among patients with pyoderma gangrenosum.
Objective
The objective of this study was to synthesize existing data on the prevalence of associated systemic diseases in patients with pyoderma gangrenosum.
Methods
We performed a systematic review and meta-analysis of observational studies in MEDLINE, EMBASE, and Scopus (1823–2017). The quality of evidence was assessed using a modified Newcastle–Ottawa Scale. A meta-analysis was performed using random-effects models to estimate pooled prevalence rates with 95% confidence intervals.
Results
Twenty-one eligible studies comprising 2611 patients with pyoderma gangrenosum were included in the quantitative synthesis. The overall random-effects pooled prevalence of associated systemic diseases was 56.8% (95% confidence interval 45.5–67.4). The leading underlying disease was inflammatory bowel disease (17.6%; 95% confidence interval 13.0–22.7), followed by arthritis (12.8%; 95% confidence interval 9.2–16.9), hematological malignancies (8.9%; 95% confidence interval 6.5–11.6), and solid malignancies (7.4%; 95% confidence interval 5.8–9.1). In 16.3% (95% confidence interval 7.7–27.1) of cases, the onset of pyoderma gangrenosum was attributed to the pathergy phenomenon.
Conclusions
More than half of patients with pyoderma gangrenosum present with a relevant underlying disease. Inflammatory bowel disease and arthritis are the most frequently associated diseases. Relative to the reported literature, the pooled prevalence of arthritis and hematological malignancies is lower, while the pooled prevalence of solid malignancies is higher. Owing to the high level of heterogeneity among most of the comparisons, results should be interpreted with caution.
https://ift.tt/2JWGnEs
Metabolism as a Target for Modulation in Autoimmune Diseases
Publication date: Available online 5 May 2018
Source:Trends in Immunology
Author(s): Nick Huang, Andras Perl
Metabolic pathways are now well recognized as important regulators of immune differentiation and activation, and thus influence the development of autoimmune diseases such as systemic lupus erythematosus (SLE). The mechanistic target of rapamycin (mTOR) has emerged as a key sensor of metabolic stress and an important mediator of proinflammatory lineage specification. Metabolic pathways control the production of mitochondrial reactive oxygen species (ROS), which promote mTOR activation and also modulate the antigenicity of proteins, lipids, and DNA, thus placing ROS at the heart of metabolic disturbances during pathogenesis of SLE. Therefore, we review here the pathways that control ROS production and mTOR activation and identify targets for safe therapeutic modulation of the signaling network that underlies autoimmune diseases, focusing on SLE.
https://ift.tt/2rnhvOA
Muscle stem cell intramuscular delivery within hyaluronan methylcellulose improves engraftment efficiency and dispersion
Source:Biomaterials, Volume 173
Author(s): Sadegh Davoudi, Chih-Ying Chin, Michael J. Cooke, Roger Y. Tam, Molly S. Shoichet, Penney M. Gilbert
Adult skeletal muscle tissue harbors the capacity for self-repair due to the presence of tissue resident muscle stem cells (MuSCs). Advances in the area of prospective MuSC isolation demonstrated the potential of cell transplantation therapy as a regenerative medicine strategy to restore strength and long-term regenerative capacity to aged, injured, or diseased skeletal muscle tissue. However, cell loss during ejection, limits to post-injection proliferation, and poor donor cell dispersion distal to the injection site are amongst hurdles to overcome to maximize MuSC transplant impact. Here, we assess a physical blend of hyaluronan and methylcellulose (HAMC) as a bioactive, shear thinning hydrogel cell delivery system to improve MuSC transplantation efficiency. Using in vivo transplantation studies, we found that the HAMC delivery system results in a >45% increase in the number of donor-derived fibers as compared to saline delivery. We demonstrate that increases in donor-derived fibers when using HAMC are attributed to increased MuSC proliferation via a CD44-independent mechanism, preventing injected cell active clearance, and supporting in vivo expansion by delaying differentiation. Furthermore, we observed a significant improvement in donor fiber dispersion when MuSCs were delivered in HAMC. Our study results suggest that HAMC is a promising muscle stem cell delivery vehicle.
https://ift.tt/2JWNaOe
Identification of a cell-penetrating peptide applicable to a protein-based transcription activator-like effector expression system for cell engineering
Publication date: August 2018
Source:Biomaterials, Volume 173
Author(s): Tomoki Takashina, Takayoshi Koyama, Satoshi Nohara, Masakatsu Hasegawa, Akira Ishiguro, Kenta Iijima, Jun Lu, Mari Shimura, Tadashi Okamura, Tetsushi Sakuma, Takashi Yamamoto, Yukihito Ishizaka
Cellular reprogramming is a promising technology in regenerative medicine, but most studies have been performed by using expression vectors. For future clinical applications, it is necessary to establish a system in which cell engineering can be manipulated without any risk of damaging the genome. Here, we identified a cell-penetrating peptide composed of 10 amino acids (RIFIHFRIGC) with nuclear trafficking activity and found that it was significantly more potent than a Tat-derived peptide or polyarginine peptide (R11). We named the peptide "nuclear trafficking peptide" (NTP) and applied it to a protein-based artificial transcription factor (NTP-ATF), which was composed of a transcription activator-like effector and transcription domain (VP64). An NTP-ATF designed to the proximal promoter region of the microRNA-302/367 cluster efficiently induced endogenous RNA expression at an extremely low concentration (0.25 nM), and repetitive treatment of mouse embryonic fibroblasts with NTP-ATF generated induced pluripotent stem-like cells, which gave chimeric mice. Together with the observation that recombinant NTP-ATF protein did not induce any apparent cytotoxicity, we propose that NTP-ATF is a promising system for cellular reprogramming applicable to regenerative medicine.
https://ift.tt/2IjZHhC
Nanopurpurin-based photodynamic therapy destructs extracellular matrix against intractable tumor metastasis
Source:Biomaterials, Volume 173
Author(s): Di Zhang, Feng Feng, Qilong Li, Xiuyu Wang, Li Yao
Nanomaterials-based photodynamic therapy (PDT) has been used to treat malignant cells. However, the intrinsic impact of nanomaterials-based PDT on mechanical properties of intractable tumor cells is not well understood. Herein, we demonstrated that the mechanical forces of Taxol-resistant tumor cells were decreased by nanopurpurin-based PDT destructing extracellular matrix (ECM), increasing therapy sensitivity and repressing tumor metastasis. Combining FIRMS and general confocal microscope, we observed that the disruption of ECM by photodynamic reaction of P18-nanoconfined liposome (P18⊂L) induced a decrease of adhesion force and biomechanical properties of Taxol-resistant cells through the attenuation of actomyosin-based contractility thereby inhibiting cell migration and metastasis in vivo. Moreover, the destroyed ECM by P18⊂L PDT increased the therapy sensitivity. A clearer understanding of the effect of nanopurpurin-based PDT on mechanical properties and behaviors of intractable tumor cells will provide new and important basis for developing new therapeutic strategies.
https://ift.tt/2JWQOrD
Non-viral delivery systems for CRISPR/Cas9-based genome editing: Challenges and opportunities
Source:Biomaterials, Volume 171
Author(s): Ling Li, Shuo Hu, Xiaoyuan Chen
In recent years, CRISPR (clustered regularly interspaced short palindromic repeat)/Cas (CRISPR-associated) genome editing systems have become one of the most robust platforms in basic biomedical research and therapeutic applications. To date, efficient in vivo delivery of the CRISPR/Cas9 system to the targeted cells remains a challenge. Although viral vectors have been widely used in the delivery of the CRISPR/Cas9 system in vitro and in vivo, their fundamental shortcomings, such as the risk of carcinogenesis, limited insertion size, immune responses and difficulty in large-scale production, severely limit their further applications. Alternative non-viral delivery systems for CRISPR/Cas9 are urgently needed. With the rapid development of non-viral vectors, lipid- or polymer-based nanocarriers have shown great potential for CRISPR/Cas9 delivery. In this review, we analyze the pros and cons of delivering CRISPR/Cas9 systems in the form of plasmid, mRNA, or protein and then discuss the limitations and challenges of CRISPR/Cas9-based genome editing. Furthermore, current non-viral vectors that have been applied for CRISPR/Cas9 delivery in vitro and in vivo are outlined in details. Finally, critical obstacles for non-viral delivery of CRISPR/Cas9 system are highlighted and promising strategies to overcome these barriers are proposed.
https://ift.tt/2Ifwx3b
Polymeric nano-shielded islets with heparin-polyethylene glycol in a non-human primate model
Source:Biomaterials, Volume 171
Author(s): Hyojun Park, Muhammad R. Haque, Jae Berm Park, Kyo Won Lee, Sanghoon Lee, Yeongbeen Kwon, Han Sin Lee, Geun-Soo Kim, Du Yeon Shin, Sang-Man Jin, Jae Hyeon Kim, Hee Jung Kang, Youngro Byun, Sung Joo Kim
Intraportal pancreatic islet transplantation incurs huge cell losses during its early stages due to instant blood-mediated inflammatory reactions (IBMIRs), which may also drive regulation of the adaptive immune system. Therefore, a method that evades IBMIR will improve clinical islet transplantation. We used a layer-by-layer approach to shield non-human primate (NHP) islets with polyethylene glycol (nano-shielded islets, NSIs) and polyethylene glycol plus heparin (heparin nano-shielded islets; HNSIs). Islets ranging from 10,000 to 20,000 IEQ/kg body weight were transplanted into 19 cynomolgus monkeys (n = 4, control; n = 5, NSI; and n = 10, HNSI). The mean C-peptide positive graft survival times were 68.5, 64 and 108 days for the control, NSI and HNSI groups, respectively (P = 0.012). HNSI also reduced the factors responsible for IBMIR in vitro. Based on these data, HNSIs in conjunction with clinically established immunosuppressive drug regimens will result in superior outcomes compared to those achieved with the current protocol for clinical islet transplantation.
https://ift.tt/2JWN35g
Humanization of bone and bone marrow in an orthotopic site reveals new potential therapeutic targets in osteosarcoma
Source:Biomaterials, Volume 171
Author(s): Ferdinand Wagner, Boris M. Holzapfel, Jacqui A. McGovern, Abbas Shafiee, Jeremy G. Baldwin, Laure C. Martine, Christoph A. Lahr, Felix M. Wunner, Thor Friis, Onur Bas, Melanie Boxberg, Peter M. Prodinger, Ali Shokoohmand, Davide Moi, Roberta Mazzieri, Daniela Loessner, Dietmar W. Hutmacher
BackgroundExisting preclinical murine models often fail to predict effects of anti-cancer drugs. In order to minimize interspecies-differences between murine hosts and human bone tumors of in vivo xenograft platforms, we tissue-engineered a novel orthotopic humanized bone model.MethodsOrthotopic humanized tissue engineered bone constructs (ohTEBC) were fabricated by 3D printing of medical-grade polycaprolactone scaffolds, which were seeded with human osteoblasts and embedded within polyethylene glycol-based hydrogels containing human umbilical vein endothelial cells (HUVECs). Constructs were then implanted at the femur of NOD-scid and NSG mice. NSG mice were then bone marrow transplanted with human CD34 + cells. Human osteosarcoma (OS) growth was induced within the ohTEBCs by direct injection of Luc-SAOS-2 cells. Tissues were harvested for bone matrix and marrow morphology analysis as well as tumor biology investigations. Tumor marker expression was analyzed in the humanized OS and correlated with the expression in 68 OS patients utilizing tissue micro arrays (TMA).ResultsAfter harvesting the femurs micro computed tomography and immunohistochemical staining showed an organ, which had all features of human bone. Around the original mouse femur new bone trabeculae have formed surrounded by a bone cortex. Staining for human specific (hs) collagen type-I (hs Col-I) showed human extracellular bone matrix production. The presence of nuclei staining positive for human nuclear mitotic apparatus protein 1 (hs NuMa) proved the osteocytes residing within the bone matrix were of human origin. Flow cytometry verified the presence of human hematopoietic cells. After injection of Luc-SAOS-2 cells a primary tumor and lung metastasis developed. After euthanization histological analysis showed pathognomic features of osteoblastic OS. Furthermore, the tumor utilized the previously implanted HUVECS for angiogenesis. Tumor marker expression was similar to human patients. Moreover, the recently discovered musculoskeletal gene C12orf29 was expressed in the most common subtypes of OS patient samples.ConclusionOhTEBCs represent a suitable orthotopic microenvironment for humanized OS growth and offers a new translational direction, as the femur is the most common location of OS. The newly developed and validated preclinical model allows controlled and predictive marker studies of primary bone tumors and other bone malignancies.
https://ift.tt/2rtd5GT
Far-red light-mediated programmable anti-cancer gene delivery in cooperation with photodynamic therapy
Source:Biomaterials, Volume 171
Author(s): Jinhui Wang, Hua He, Xin Xu, Xiao Wang, Yongbing Chen, Lichen Yin
Effective anti-cancer therapy is hurdled by the complicated extracellular and intracellular barriers, and thus a smart gene vector that can enable programmable gene delivery is highly demanded. Photo-manipulation of gene delivery processes features spatial and temporal precision, while majority of current strategies utilizes short-wavelength UV/visible light with poor tissue penetration or high-power-density near-infrared (NIR) light that would cause undesired heat damage. Herein, an ROS-degradable polycation was designed and co-delivered with a photosensitizer (PS), thus realizing photo-programmable gene delivery using far-red light (661 nm) at low optical power density (down to 5 mW cm−2). Thioketal-crosslinked polyethylenimine (TK-PEI) was synthesized to condense p53 gene to form nanocomplexes (NCs), and hyaluronic acid (HA) modified with pheophytin a (Pha) was coated onto NCs to enhance their colloidal stability and enable cancer cell targeting. Short-time (8-min) light irradiation produced non-lethal amount of ROS to disrupt the endosomal membranes and facilitate p53 gene release via degradation of TK-PEI, which collectively enhanced p53 expression levels toward anti-cancer gene therapy. Long-time (30-min) light irradiation at the post-transfection state generated lethal amount of ROS, which cooperatively killed cancer cells to strengthen p53 gene therapy. To the best of our knowledge, this study represents the first example of an "one stone, three birds" approach to realize cooperative anti-cancer gene therapy using low-power-density, long-wavelength visible light as a single stimulus.
https://ift.tt/2rmJ8YF
Highly enhanced cancer immunotherapy by combining nanovaccine with hyaluronidase
Publication date: July 2018
Source:Biomaterials, Volume 171
Author(s): Xiuwen Guan, Jie Chen, Yingying Hu, Lin Lin, Pingjie Sun, Huayu Tian, Xuesi Chen
Tumor vaccine has been one of the research hotspots for cancer immunotherapy in recent years. By introducing tumor antigens into the body, the patient's own immune system will be specifically activated to induce effective immune responses for controlling or eliminating the malignant tumor cells. In this study, a simple nanovaccine was developed to induce antigen-specific anti-tumor immune responses. Polycationic polyethylenimine (PEI) was utilized to co-deliver the antigen ovalbumin (OVA) and the adjuvant unmethylated cytosine-phosphate-guanine (CpG) by electrostatic binding. The positively charged PEI could be beneficial to augment the PEI/CpG/OVA nanovaccine uptake in dendritic cells (DCs) and facilitate the endosomal escape of the nanovaccine for antigen delivering into the cytoplasm. The nanovaccine showed significant stimulation on DCs' maturation in vitro, and it was further applied for in vivo anti-tumor immunotherapy. To enhance the tumor infiltration of the nanovaccine-generated tumor-specific T cells, hyaluronidase (HAase) was employed to increase the permeability of the tumor tissues by breaking down the hyaluronan (HA) in the extracellular matrix (ECM) of tumors. Highly enhanced in vivo anti-tumor therapeutic efficiency was achieved by combining the PEI/CpG/OVA nanovaccine with HAase, which was attributed to the increased quantity of OVA-specific T cells in tumor tissues. The combination of nanovaccine with HAase has offered a simple and efficient strategy for inducing powerful anti-tumor effect in cancer immunotherapy.
Graphical abstract
https://ift.tt/2JWBLOE
Spatially confined induction of endochondral ossification by functionalized hydrogels for ectopic engineering of osteochondral tissues
Source:Biomaterials, Volume 171
Author(s): Chiara Stüdle, Queralt Vallmajó-Martín, Alexander Haumer, Julien Guerrero, Matteo Centola, Arne Mehrkens, Dirk J. Schaefer, Martin Ehrbar, Andrea Barbero, Ivan Martin
Despite the various reported approaches to generate osteochondral composites by combination of different cell types and materials, engineering of templates with the capacity to autonomously and orderly develop into cartilage-bone bi-layered structures remains an open challenge. Here, we hypothesized that the embedding of cells inducible to endochondral ossification (i.e. bone marrow derived mesenchymal stromal cells, BMSCs) and of cells capable of robust and stable chondrogenesis (i.e. nasal chondrocytes, NCs) adjacent to each other in bi-layered hydrogels would develop directly in vivo into osteochondral tissues. Poly(ethylene glycol) (PEG) hydrogels were functionalized with TGFβ3 or BMP-2, enzymatically polymerized encapsulating human BMSCs, combined with a hydrogel layer containing human NCs and ectopically implanted in nude mice without pre-culture. The BMSC-loaded layers reproducibly underwent endochondral ossification and generated ossicles containing bone and marrow. The NC-loaded layers formed cartilage tissues, which (under the influence of BMP-2 but not of TGFβ3 from the neighbouring layer) remained phenotypically stable. The proposed strategy, resulting in orderly connected osteochondral composites, should be further assessed for the repair of osteoarticular defects and will be useful to model developmental processes leading to cartilage-bone interfaces.
https://ift.tt/2Id8x0G
Combinational strategy for high-performance cancer chemotherapy
Publication date: July 2018
Source:Biomaterials, Volume 171
Author(s): Si-Yong Qin, Yin-Jia Cheng, Qi Lei, Ai-Qing Zhang, Xian-Zheng Zhang
The clinical outcomes of conventional mono-chemotherapy of cancers are usually far from satisfactory due to some issues such as tumor heterogeneity and resistance to chemotherapeutic drugs. With the increasing knowledge of molecular signal pathways and pathological mechanisms involved in the initiation and progression of cancers, collaborative strategies have been elaborated to optimize therapeutic outcomes. This review surveys the most recent advances in combination therapy including combination chemotherapy, chemotherapy plus gene therapy, chemotherapy plus phototherapy, as well as chemotherapy plus immunotherapy. Additionally, chemotherapy-involved multiple therapy that merges various therapeutic modalities is also presented. We try to elicit the rationales of applying these combinational formulations for cancer chemotherapy, which might provide new guidelines for high-performance cancer treatments.
Graphical abstract
https://ift.tt/2JSBpZu
UGT1A polymorphisms associated with worse outcome in colorectal cancer patients treated with irinotecan-based chemotherapy
Abstract
Purpose
To investigate the association between UDP-glucuronosyltransferase (UGT)1A polymorphisms and irinotecan-treatment efficacy in a Chinese population with metastatic colorectal cancer (mCRC).
Methods
The present study was based on a prospective multicenter trial of Chinese mCRC patients treated with irinotecan-based chemotherapy (NCT01282658, registered at http://www.clinicaltrials.gov). Fifteen single-nucleotide polymorphisms (SNPs) in four UGT1A genes were selected for genotyping in 164 patients. Kaplan–Meier and Cox regression analyses were used to assess the association between potential signatures and survival outcome.
Results
We found that UGT1A1*28 variant genotype was significantly associated with decreased progression-free survival (PFS) [adjusted hazard ratio (HR), 1.803; 95% confidence interval (CI), 1.217–2.671] and overall survival (OS) (adjusted HR 1.979; 95% CI 1.267–3.091) compared with wild-type genotype. Patients carrying (TA)7 allele showed a median PFS of 7.5 (95% CI 5.5–9.6) months compared with 9.8 (95% CI 8.6–10.9) months for patients with wild-type genotype. Median OSs were 13.3 (95% CI 10.3–16.2), and 20.8 (95% CI 18.7–23.0) months for (TA)6/7 or (TA)7/7, and (TA)6/6 patients, respectively. Similarly but more significantly, the copy number of haplotype III (composed by rs3755321-T, rs3821242-C, rs4124874-G and rs3755319-C) constructed among the selected SNPs also correlated with survival outcome.
Conclusions
UGT1A polymorphisms are predictive of survival outcome of irinotecan-treated Chinese mCRC patients. After validation, UGT1A polymorphisms might be helpful in facilitating stratification of mCRC patients for individualized treatment options.
https://ift.tt/2HRD3d9
Phase II trial of induction chemotherapy of pemetrexed plus split-dose cisplatin followed by pemetrexed maintenance for untreated non-squamous non-small-cell lung cancer
Abstract
Purpose
We conducted a phase II trial to evaluate the efficacy and safety of induction chemotherapy of pemetrexed plus split-dose cisplatin followed by pemetrexed maintenance for advanced non-squamous non-small-cell lung cancer (NSCLC).
Methods
Patients with advanced or recurrent untreated non-squamous NSCLC received split-dose cisplatin (40 mg/m2, days 1 and 8) plus pemetrexed (500 mg/m2, day 1) tri-weekly. After four cycles of induction, patients without disease progression received pemetrexed maintenance until disease progression or unacceptable toxicity. The primary endpoint was the 1-year survival rate. The secondary endpoints were progression-free survival (PFS), overall survival (OS), response in induction phase, and safety.
Results
From February 2012 to September 2014, 53 assessable patients were enrolled in this study. Thirty-eight (71.7%) patients completed induction therapy, while 35 (66.0%) received maintenance therapy. The 1-year survival rate was 67.7%. The median PFS and OS were 5.3 and 18.6 months, respectively. The response rate and disease control rate (DCR) during the induction phase were 37.7 and 86.8%, respectively. Eight patients (15.1%) discontinued the therapy due to adverse events (AEs) during the induction phase, but both hematological and non-hematological AEs were infrequent.
Conclusions
Treatment with induction chemotherapy of pemetrexed plus split-dose cisplatin showed a promising 1-year survival rate, DCR, and transition rate into maintenance phase. This regimen is feasible and well-tolerated. A phase III study comparing this regimen with conventional tri-weekly regimen is warranted.
https://ift.tt/2KE9nlG
Expression of M2 macrophage markers YKL-39 and CCL18 in breast cancer is associated with the effect of neoadjuvant chemotherapy
Abstract
Purpose
High activity of enzyme TOP2a in tumor cells is known to be associated with sensitivity to anthracycline chemotherapy, but 20% of such patients do not show clinical response. Tumor microenvironment, including tumor-associated macrophages (TAM), is an essential factor defining the efficiency of chemotherapy. In the present study, we analyzed the expression of M2 macrophage markers, YKL-39 and CCL18, in tumors of breast cancer patients received anthracycline-based NAC.
Methods
Patients were divided into two groups according to the level of doxorubicin sensitivity marker TOP2a: DOX-Sense and DOX-Res groups. Expression levels of TOR2a, CD68, YKL-39 and CCL18 genes were analyzed by qPCR, the amplification of TOR2a gene locus was assessed by the microarray assay. Clinical and pathological responses to neoadjuvant chemotherapy were assessed.
Results
We found that the average level of TOP2a expression in patients of DOX-Sense group was almost 10 times higher than in patients of DOX-Res group, and the expression of CD68 was 3 times higher in the DOX-Sense group compared to DOX-Res group. We demonstrated that expression levels of M2-derived cytokines but not the amount of TAM is indicative for clinical and pathological chemotherapy efficacy in breast cancer patients. Out of 8 patients from DOX-Sense group who did not respond to neoadjuvant chemotherapy (NAC), 7 patients had M2+ macrophage phenotype (YKL-39+CCL18− or YKL-39−CCL18+) and only one patient had M2− macrophage phenotype (YKL-39−CCL18−). In DOX-Res group, out of 14 patients who clinically responded to NAC 9 patients had M2− phenotype and only 5 patients had M2+ macrophage phenotype. Among pathological non-responders in DOX-Sense group, 19 (82%) patients had M2+ tumor phenotype and only 4 (18%) patients had M2− phenotype. In DOX-Res group, all 5 patients who pathologically responded to NAC had M2 phenotype (YKL-39−CCL18−). Unlike the clinical response to NAC, the differences in the frequency of M2+ and M2− phenotypes between pathologically responding and non-responding patients within DOX-Sense and DOX-Res groups were statistically significant.
Conclusions
Thus, we showed that in patients with breast cancer who received anthracycline-containing NAC the absence of clinical response is associated with the presence of M2+ macrophage phenotype (YKL-39-CCL18 + or YKL-39 + CCL18-) based on TOP2a overexpression data.
https://ift.tt/2FJrtz3
Sunitinib does not acutely alter left ventricular systolic function, but induces diastolic dysfunction
Abstract
Purpose
Cancer chemotherapies have improved the prognosis of cancer patients in recent years; however, their side effects on the cardiovascular systems have emerged as a major concern in the field of both cardiology and oncology. In particular, multi-targeted tyrosine kinase inhibitors are known to induce various types of cardiovascular adverse events including hypertension, QT-interval prolongation and heart failure, but their underlying mechanisms remain elusive. To explore how to better predict such drug-induced cardiovascular adverse events, we assessed the electropharmacological effects of sunitinib using the halothane-anesthetized dogs (n = 5), while plasma concentrations of cardiac enzymes including aspartate aminotransferase, lactate dehydrogenase, creatinine kinase and cardiac troponin I were measured.
Methods
Sunitinib was intravenously administered at 0.01 and 0.1 mg/kg for 10 min with 20 min interval.
Results
Sunitinib decreased the amplitude of maximum downstroke velocity of the left ventricular pressure, prolonged the isovolumic relaxation time and increased the left ventricular end-diastolic pressure in a dose-related manner without affecting the other cardiohemodynamic and electrophysiological variables. More importantly, sunitinib significantly elevated cardiac troponin I level for 30–60 min after the high dose without altering the other biomarkers.
Conclusions
Monitoring of the cardiac diastolic function together with cardiac troponin I after the start of sunitinib administration may become a reliable measure to predict the onset of sunitinib-induced cardiovascular adverse events.
https://ift.tt/2reknNJ
Exposure–response relationship for ramucirumab from the randomized, double-blind, phase 3 REVEL trial (docetaxel versus docetaxel plus ramucirumab) in second-line treatment of metastatic non-small cell lung cancer
Abstract
Purpose
Ramucirumab plus docetaxel improved survival in REVEL, a randomized phase 3 trial for patients with Stage IV non-small cell lung cancer after standard platinum-based chemotherapy. This exploratory analysis evaluated the exposure–response relationship of ramucirumab from REVEL.
Methods
Patients received ramucirumab (10 mg/kg) or placebo plus docetaxel (75 mg/m2) every 3 weeks. Pharmacokinetic samples were collected. A population pharmacokinetic analysis predicted ramucirumab minimum concentration after first-dose administration (Cmin,1) and average concentration at steady state (Cave,ss). Predicted Cmin,1 and Cave,ss were used to evaluate the relationship between ramucirumab exposure and efficacy and safety, respectively. Exposure–efficacy was assessed by Kaplan–Meier and Cox regression analyses; exposure–safety was assessed by ordered categorical analyses.
Results
Analyses included 376 patients treated with ramucirumab plus docetaxel and 366 patients treated with placebo plus docetaxel (364 for safety population). After adjusting for corresponding prognostic factors, the association between overall survival (OS) and Cmin,1 was statistically significant (p = 0.0110), although progression-free survival (PFS) showed a marginal association (p = 0.0515). At high ramucirumab exposures (Cmin,1), greater improvements (smaller hazard ratios) were seen for OS and PFS when stratified by Cmin,1 exposure quartiles. A statistically significant correlation was observed between ramucirumab Cave,ss and grade ≥ 3 febrile neutropenia and hypertension.
Conclusions
An association was observed between ramucirumab exposure and efficacy. Higher ramucirumab exposure was associated with improved clinical outcomes and increased toxicity in this analysis. Two exposure–response prospective randomized trials are being conducted to address causation (NCT02443883 and NCT02514551), with encouraging preliminary results (Ajani et al. in Ann Oncol 28:abstr 698P, 2017).
https://ift.tt/2HKdpuX
EML4–ALK rearrangement in squamous cell carcinoma shows significant response to anti-ALK inhibitor drugs crizotinib and alectinib
Abstract
EML4–ALK alterations are more common in adenocarcinomas and are rarely found in squamous cell histology. In documented cases, the majority of EML4–ALK translocations are identified in squamous cell histology and occur in patients with no or light smoking history. We report an EML4–ALK4 translocation in a 50-year-old patient with squamous cell carcinoma and an 18 pack-year smoking history. The patient had a near complete response in the CNS to alectinib treatment. Our observation suggests that EML4–ALK genomic testing may be clinically useful in patients with heavy smoking history.
https://ift.tt/2HXvIJc
EGFL7 and RASSF1 promoter hypermethylation in epithelial ovarian cancer
Source:Cancer Genetics, Volumes 224–225
Author(s): Yanisa Rattanapan, Veerawat Korkiatsakul, Adcharee Kongruang, Takol Chareonsirisuthigul, Budsaba Rerkamnuaychoke, Anna Wongkularb, Sarikapan Wilailak
DNA methylation is one of the epigenetic mechanisms associated with gene expression and plays a key role as in activation and deactivation of oncogenes and tumor suppressor genes, respectively. This study employed DNA methylation array to identify methylated genes which are highly correlated with various phenotypes of epithelial ovarian cancer (EOC) in Thai patients and to quantify promoter CpG-island methylation of candidate genes. Tissues from patients with serous and non-serous EOC showed significantly higher promoter methylation of EGFL7 and RASSF1 compared to benign cases. These results indicate the potential of investigating promoter CpG-island methylation of cancer-associated genes as biomarkers of disease progression and even possibly of early detection.
https://ift.tt/2jwVcSX
Influence of side-effects on early therapy persistence with letrozole in post-menopausal patients with early breast cancer: Results of the prospective EvAluate-TM study
Source:European Journal of Cancer, Volume 96
Author(s): N. Nabieva, T. Fehm, L. Häberle, J. de Waal, M. Rezai, B. Baier, G. Baake, H.-C. Kolberg, M. Guggenberger, M. Warm, N. Harbeck, R. Wuerstlein, J.-U. Deuker, P. Dall, B. Richter, G. Wachsmann, C. Brucker, J.W. Siebers, M. Popovic, T. Kuhn, C. Wolf, H.-W. Vollert, G.-P. Breitbach, W. Janni, R. Landthaler, A. Kohls, D. Rezek, T. Noesselt, G. Fischer, S. Henschen, T. Praetz, V. Heyl, T. Kühn, T. Krauss, C. Thomssen, A. Hohn, H. Tesch, C. Mundhenke, A. Hein, C.C. Hack, K. Schmidt, E. Belleville, S.Y. Brucker, S. Kümmel, M.W. Beckmann, D. Wallwiener, P. Hadji, P.A. Fasching
BackgroundEndocrine treatment (ET) with an aromatase inhibitor (AI) is the treatment of choice in post-menopausal patients with hormone receptor–positive early breast cancer (EBC). However, adverse events (AEs) often lead to treatment discontinuation. This analysis aimed to identify side-effects that lead to patients failing to persist with letrozole treatment.Patients and methodsPost-menopausal hormone receptor–positive EBC patients starting ET with letrozole were enroled in EvAluate-TM, a non-interventional study. Information regarding treatment compliance and persistence was gathered in months 6 and 12. Persistence was defined as the time from 30 d after the start to the end of treatment. The influence on persistence of musculoskeletal syndrome, menopausal disorder, sleep disorder and other AEs within the first 30 d was analysed using Cox regression analyses.ResultsAmong 3887 patients analysed, the persistence rate after 12 months was >85%. In all, 568 patients (14.6%) discontinued the treatment, 358 of whom (63.0%) did so only because of side-effects. The main AEs influencing persistence were musculoskeletal symptoms (hazard ratio [HR] 2.55; 95% confidence interval [CI], 1.90–3.42), sleep disorders (HR 1.95; 95% CI, 1.41–2.70) and other AEs (HR 2.03; 95% CI, 1.51–2.73). Menopausal disorder was not associated with non-persistence (HR 1.17; 95% CI, 0.74–1.84).ConclusionsThese results suggest that side-effects of AIs such as musculoskeletal syndrome and sleep disorder lead to ET discontinuation within the first treatment year in significant numbers of EBC patients. Compliance programmes adapted for subgroups that are at risk for early non-persistence might help to ensure the recommended therapy duration.Clinical Trials NumberCFEM345DDE19.
https://ift.tt/2rmncMs
A randomised-controlled trial of 1-year adjuvant chemotherapy with oral tegafur–uracil versus surgery alone in stage II colon cancer: SACURA trial
Source:European Journal of Cancer, Volume 96
Author(s): Chu Matsuda, Megumi Ishiguro, Satoshi Teramukai, Yoshiki Kajiwara, Shoichi Fujii, Yusuke Kinugasa, Yoshihiko Nakamoto, Masanori Kotake, Yoshiyuki Sakamoto, Kiyotaka Kurachi, Atsuyuki Maeda, Koji Komori, Naohiro Tomita, Yasuhiro Shimada, Keiichi Takahashi, Kenjiro Kotake, Masahiko Watanabe, Hidetaka Mochizuki, Yoko Nakagawa, Kenichi Sugihara
BackgroundEfficacy of adjuvant chemotherapy in patients with stage II colon cancer is still controversial. The SACURA trial is a randomised-controlled study evaluating the superiority of 1-year adjuvant treatment with oral tegafur–uracil (UFT) to surgery alone for stage II colon cancer.MethodsPatients were randomly assigned to the surgery-alone group or UFT group (UFT at 500–600 mg/day for 5 days, followed by 2-day rest, for 1 year). The primary end-point was disease-free survival (DFS). Target sample size was 2000, determined with one-sided alpha of 0.05, power of 0.9 and assumed hazard ratio (HR) 0.729.ResultsA total of 1982 patients (997 in the surgery-alone group and 985 in the UFT group) were analysed. Median follow-up was 69.5 months, median age was 66 years and for stage IIA/IIB/IIC, the distribution was 84%/13%/3%.The 5-year DFS rate was 78.4% in the surgery-alone group and 80.2% in the UFT group. The HR for DFS was 0.91 (95% confidence interval [CI], 0.75–1.10; p = 0.31); superiority of UFT was not demonstrated. Approximately 9% of patients experienced second cancers, which consist 40.7% of the DFS events. The 5-year relapse-free and overall survival rates of the surgery-alone and UFT group were 84.6% and 87.2% (HR, 0.82; 95% CI, 0.65–1.04) and 94.3% and 94.5% (HR, 0.93; 95% CI, 0.66–1.31), respectively. Subgroup analysis failed to disclose superiority in prognosis of adding UFT to the patients with risk factors for recurrence.ConclusionsSuperiority of 1-year adjuvant UFT over surgery alone was not demonstrated in stage II colon cancer. Patients with risk factors for recurrence did not benefit from UFT.Trial registrationClinicalTrials. Gov. #NCT00392899.
https://ift.tt/2KDdCxy
Efficacy and safety of single-agent pan-human epidermal growth factor receptor (HER) inhibitor dacomitinib in locally advanced unresectable or metastatic skin squamous cell cancer
Source:European Journal of Cancer, Volume 97
Author(s): S. Cavalieri, F. Perrone, R. Miceli, P.A. Ascierto, L.D. Locati, C. Bergamini, R. Granata, S. Alfieri, C. Resteghini, D. Galbiati, A. Busico, N. Paielli, R. Patuzzo, A. Maurichi, G. Gallino, R. Ruggeri, L. Mariani, M. Palla, L. Licitra, P. Bossi
BackgroundIn recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial.MethodsPatients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC.ResultsForty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3–4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup.ConclusionsIn sSCC, dacomitinib showed activity similar to what was observed with anti–epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio.
https://ift.tt/2rphdXv
A new look at the International Duration Evaluation of Adjuvant therapy (IDEA) classification—Defining novel predictive and prognostic markers in stage III colon cancer
Source:European Journal of Cancer, Volume 96
Author(s): Ofer Margalit, Ronac Mamtani, Yu-Xiao Yang, Kim A. Reiss, Talia Golan, Naama Halpern, Dan Aderka, Bruce Giantonio, Einat Shacham-Shmueli, Ben Boursi
BackgroundThe International Duration Evaluation of Adjuvant therapy (IDEA) pooled analysis compared 3 to 6 months of adjuvant chemotherapy for stage III colon cancer. The overarching goal was to reduce chemotherapy-related toxicity, mainly oxaliplatin-induced neuropathy. Patients were classified into low-risk and high-risk groups, suggesting that low-risk patients may be offered only 3 months of treatment. We aimed to evaluate the benefit of monotherapy versus doublet chemotherapy in low and high IDEA risk groups.MethodsUsing the National Cancer Database (2004–2014), we identified 56,728 low-risk and 47,557 high-risk individuals with stage III colon cancer, according to the IDEA classification. We used multivariate Cox regression to evaluate the magnitude of survival differences between IDEA risk groups, according to treatment intensity (doublet versus monotherapy). In a secondary analysis, we examined the prognostic and predictive value of subgroups of age, tumour sidedness and lymph node ratio (LNR).ResultsLow and high IDEA risk groups derived similar benefit from doublet adjuvant chemotherapy as compared with monotherapy, with hazard ratios (HRs) of 0.83 (95% confidence interval [CI] 0.79–0.86) and 0.80 (95% CI 0.78–0.83), respectively. The only subpopulations that did not benefit from doublet chemotherapy were low-risk patients older than 72 years (HR = 0.95, 95% CI 0.90–1.01) and high-risk patients older than 85 years (HR = 0.90, 95% CI 0.77–1.05). LNR and tumour sidedness were shown as additional prognostic, but not predictive, factors within the IDEA risk groups.ConclusionsIDEA risk classification per se does not predict for treatment benefit from doublet chemotherapy in stage III colon cancer. However, omission of oxaliplatin can be considered in IDEA low-risk patients older than 72 years.
https://ift.tt/2KGvY0S
Persisting inequalities in survival patterns of childhood neuroblastoma in Southern and Eastern Europe and the effect of socio-economic development compared with those of the US
Source:European Journal of Cancer, Volume 96
Author(s): Paraskevi Panagopoulou, Marios K. Georgakis, Margarita Baka, Maria Moschovi, Vassilios Papadakis, Sophia Polychronopoulou, Maria Kourti, Emmanuel Hatzipantelis, Eftichia Stiakaki, Helen Dana, Athanasios Tragiannidis, Evdoxia Bouka, Luis Antunes, Joana Bastos, Daniela Coza, Anna Demetriou, Domenic Agius, Sultan Eser, Raluca Gheorghiu, Mario Šekerija, Maciej Trojanowski, Tina Žagar, Anna Zborovskaya, Anton Ryzhov, Nick Dessypris, Daniel Morgenstern, Eleni Th Petridou
AimNeuroblastoma outcomes vary with disease characteristics, healthcare delivery and socio-economic indicators. We assessed survival patterns and prognostic factors for patients with neuroblastoma in 11 Southern and Eastern European (SEE) countries versus those in the US, including—for the first time—the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumours (NARECHEM-ST)/Greece.MethodsOverall survival (OS) was calculated in 13 collaborating SEE childhood cancer registries (1829 cases, ∼1990–2016) and Surveillance, Epidemiology, and End Results (SEER), US (3072 cases, 1990–2012); Kaplan–Meier curves were used along with multivariable Cox regression models assessing the effect of age, gender, primary tumour site, histology, Human Development Index (HDI) and place of residence (urban/rural) on survival.ResultsThe 5-year OS rates varied widely among the SEE countries (Ukraine: 45%, Poland: 81%) with the overall SEE rate (59%) being significantly lower than in SEER (77%; p < 0.001). In the common registration period within SEE (2000–2008), no temporal trend was noted as opposed to a significant increase in SEER. Age >12 months (hazard ratio [HR]: 2.8–4.7 in subsequent age groups), male gender (HR: 1.1), residence in rural areas (HR: 1.3), living in high (HR: 2.2) or medium (HR: 2.4) HDI countries and specific primary tumour location were associated with worse outcome; conversely, ganglioneuroblastoma subtype (HR: 0.28) was associated with higher survival rate.ConclusionsAllowing for the disease profile, children with neuroblastoma in SEE, especially those in rural areas and lower HDI countries, fare worse than patients in the US, mainly during the early years after diagnosis; this may be attributed to presumably modifiable socio-economic and healthcare system performance differentials warranting further research.
https://ift.tt/2rphf1z
Reporting of patient characteristics and stratification factors in phase 3 trials investigating first-line systemic treatment of metastatic colorectal cancer: A systematic review
Source:European Journal of Cancer, Volume 96
Author(s): Kaitlyn K.H. Goey, Remi Mahmoud, Halfdan Sørbye, Bengt Glimelius, Claus-Henning Köhne, Daniel J. Sargent, Cornelis J.A. Punt, Martijn G.H. van Oijen, Miriam Koopman
BackgroundPatient characteristics and stratification factors are important factors influencing trial outcomes. Uniform reporting on these parameters would facilitate cross-study comparisons and extrapolation of trial results to clinical practice. In 2007, standardisation on patient characteristics reporting and stratification in metastatic colorectal cancer (mCRC) trials was proposed. We investigated the reporting of prognostic factors and implementation of this proposal in mCRC trials published from 2005 to 2016.MethodsWe searched PubMed and Embase (January 2005 – June 2016) for first-line phase 3 mCRC trials. Patient characteristics reporting and use of stratification factors were extracted and analysed for adherence to the proposal from 2007.ResultsSixty-seven trials (35,315 patients) were identified, reporting 48 different patient characteristics (median: 9 [range: 5–18] per study). Age, gender, performance status (PS), primary tumour site and adjuvant chemotherapy were frequently reported (87%–100%), in contrast to laboratory values, such as alkaline phosphatase, lactate dehydrogenase and white blood cell count (10%–25%). We identified 29 different stratification factors (median: 3 [range: 1–9] per study). The most common strata were PS and treatment centre (>60%). A median of 8/12 (range: 4–11) of the proposed parameters was reported. Although the percentage of studies reporting each factor slightly increased over time, there was no significant correlation between publication year and adherence to the proposal from 2007.ConclusionsWe observed persistent heterogeneity in the reporting of patient characteristics and use of stratification factors in first-line mCRC trials. The proposal from 2007 has not led to increased uniformity of patient characteristics reporting and use of stratification over time. There is an urgent need to address this issue to improve the interpretation of trial results.
https://ift.tt/2HRaws4
Diagnostic value of 18F-fluordesoxyglucose positron emission tomography for patients with brain metastasis from unknown primary site
Source:European Journal of Cancer, Volume 96
Author(s): Fabian Wolpert, Michael Weller, Anna Sophie Berghoff, Elisabeth Rushing, Lisa Michaela Füreder, Gregory Petyt, Henning Leske, Nicolaus Andratschke, Luca Regli, Marian Christoph Neidert, Roger Stupp, Rolf Stahel, Reinhard Dummer, Thomas Frauenfelder, Patrick Roth, Nicolas Reyns, Philipp Antonio Kaufmann, Matthias Preusser, Emilie Le Rhun
BackgroundIn 30% of patients with brain metastasis (BM), neurological symptoms are the first clinical manifestation of systemic malignancy, referred to as BM from cancer of unknown primary site (BM-CUPS). Here, we define the diagnostic value of 18F-fluordesoxyglucose positron emission tomography (FDG-PET/CT) in the workup of BM-CUPS.MethodsWe screened 565 patients operated for BM at the University Hospital Zurich and identified 64 patients with BM-CUPS with data on both FDG-PET/CT and contrast-enhanced chest/abdomen computed tomography (CT) available at BM diagnosis. A cohort of 125 patients with BM-CUPS from Lille and Vienna was used for validation.ResultsFDG-PET/CT was not superior to chest/abdomen CT in localising the primary lesion in the discovery cohort, presumably because most primary tumours were lung cancers. However, FDG-PET/CT identified additional lesions suspicious of extracranial metastases in 27 of 64 patients (42%). The inclusion of FDG-PET/CT findings shifted the graded prognostic assessment (GPA) score from 3 with CT alone to 2.5 for PET/CT (p = 3.8 × 10−5, Wilcoxon's test), resulting in a predicted survival of 5.3 versus 3.8 months (p = 6.1 × 10−5; Wilcoxon's test). All observations were confirmed in the validation cohort.ConclusionsLung cancers are the most common primary tumour in BM-CUPS; accordingly, CT alone shows similar overall sensitivity for detecting the primary tumour as FDG-PET/CT. Yet, FDG-PET/CT improves the accuracy of staging by detecting more metastases, reflected by decreased GPA scores and decreased predicted survival. Therefore, randomised trials on patients with BM should standardise methods of staging, notably when stratifying for GPA.
https://ift.tt/2rneWfj
Comparable results of autologous and allogeneic haematopoietic stem cell transplantation for adults with Philadelphia-positive acute lymphoblastic leukaemia in first complete molecular remission: An analysis by the Acute Leukemia Working Party of the EBMT
Source:European Journal of Cancer, Volume 96
Author(s): Sebastian Giebel, Myriam Labopin, Michael Potter, Xavier Poiré, Henrik Sengeloev, Gerard Socié, Anne Huynh, Boris V. Afanasyev, Urs Schanz, Olle Ringden, Peter Kalhs, Dietrich W. Beelen, Antonio M. Campos, Tamás Masszi, Jonathan Canaani, Mohamad Mohty, Arnon Nagler
BackgroundAllogeneic haematopoietic stem cell transplantation (alloHSCT) is considered a standard treatment for patients with Philadelphia chromosome–positive acute lymphoblastic leukaemia (Ph+ ALL) achieving complete remission after induction containing tyrosine kinase inhibitors (TKIs).MethodsWe retrospectively compared results of myeloablative alloHSCT from either matched sibling donor (MSD) or unrelated donor (URD) with autologous (auto) HSCT for adults with Ph+ ALL in molecular remission, treated between 2007 and 2014.ResultsIn univariate analysis, the incidence of relapse at 2 years was 47% after autoHSCT, 28% after MSD-HSCT and 19% after URD-HSCT (P = 0.0002). Respective rates of non-relapse mortality were 2%, 18%, and 22% (P = 0.001). The probabilities of leukaemia-free survival were 52%, 55% and 60% (P = 0.69), while overall survival rates were 70%, 70% and 69% (P = 0.58), respectively. In multivariate analysis, there was a trend towards increased risk of overall mortality after MSD-HSCT (hazard ratio [HR], 1.5, P = 0.12) and URD-HSCT (HR, 1.6, P = 0.08) when referred to autoHSCT. The use of total body irradiation (TBI)–based regimens was associated with reduced risk of relapse (HR, 0.65, P = 0.02) and overall mortality (HR, 0.67, P = 0.01).ConclusionIn the era of TKIs, outcomes of myeloablative autoHSCT and alloHSCT for patients with Ph+ ALL in first molecular remission are comparable. Therefore, autoHSCT appears to be an attractive treatment option potentially allowing for circumvention of alloHSCT sequelae. Irrespective of the type of donor, TBI-based regimens should be considered the preferable type of conditioning for Ph+ ALL.
https://ift.tt/2HSAETE
Detection of immune-related adverse events by medical imaging in patients treated with anti-programmed cell death 1
Source:European Journal of Cancer, Volume 96
Author(s): Ahmed Mekki, Laurent Dercle, Philip Lichtenstein, Aurélien Marabelle, Jean-Marie Michot, Olivier Lambotte, Jérôme Le Pavec, Eleonora De Martin, Corinne Balleyguier, Stéphane Champiat, Samy Ammari
BackgroundProgrammed death receptor-1 blocking antibodies (anti-PD1) are a new standard of care in many cancer types. Patients benefit from improved survival but have the risk of immune-related adverse events (irAE). We evaluated if medical imaging procedures, used for anti-tumour response assessment, can detect irAEs.Materials and methodsAll consecutive patients treated with anti-PD1 and with a medical imaging acquisition performed within 2 weeks with irAEs ≥2 were retrospectively included. Data were gathered from June 2014 to February 2017, and a central review was performed. The primary and secondary end-points were i) to evaluate the overall detection rate of irAEs by medical imaging and ii) to provide a comprehensive radiological description of irAEs.ResultsFifty-three patients (31 women, 22 men; average age: 61 years) were included. The primary tumour was melanoma (n = 32), lung cancer (n = 18) and other (n = 3). Patients were treated with nivolumab (n = 27) or pembrolizumab (n = 26). Of 74 medical imaging procedures analysed (ratio = 1.4 medical imaging per patient), 55 irAE were detected. The detection rate was overall: 74% (95 confidence interval: 63–84%), positron emission tomography with 18F-fludeoxyglucose integrated with computed tomography (18F-FDG PET/CT): 83% (n = 10/12), magnetic resonance imaging: 83% (n = 5/6), computed tomography scan: 79% (n = 19/24), ultrasonography: 70% (n = 19/27), standard X-rays: 40% (n = 2/5), lung/mediastinum: 100% (n = 7/7), enterocolitis: 100% (n = 8/8), hypophysitis: 100% (n = 3/3), thyroiditis: 75% (n = 15/20), hepatitis: 67% (n = 2/3), arthralgia or arthritis: 40% (n = 2/5) and pancreas: 28% (n = 2/7).ConclusionMedical imaging detected 74% of irAE in patients treated with anti-PD1. Beyond response assessment, medical imaging can detect irAE and guide towards specific management. We described the most frequent sites and patterns of imaging findings.
https://ift.tt/2rnouqQ
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Summary Insulinomas are rare neuroendocrine tumours that classically present with fasting hypoglycaemia. This case report discusses an un...
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