Prognostic impact of vascular and lymphovascular invasion in early lung cancer

Background The prognostic significance of vascular and lymphatic invasion in non-small-cell lung cancer is under continuous debate. We analyzed the effect of tumor aggressiveness (lymphatic and/or vessel invasion) on survival and relapse in stage I and II non-small-cell lung cancer. Methods We retrospectively analyzed prospectively collected data of 457 patients with stage I and II non-small-cell lung cancer from 1998 to 2008. Specimens were analyzed for intratumoral vascular invasion and lymphovascular space invasion. Overall survival and disease-free survival were estimated using the Kaplan-Meier method, and differences were determined by the logrank test. Cox regression analysis was performed to identify independent risk factors. Results: The incidence of intratumoral vascular invasion was 23.4%, and this correlated significantly with grade of differentiation, visceral pleural involvement, lymphovascular space invasion, and N status. The incidence of lymphovascular space invasion was 5.5%, and this correlated significantly with grade of differentiation, lymph nodes involved, and intratumoral vascular invasion. On multivariate analyses, intratumoral vascular invasion proved to be an significant independent risk factor for overall survival but not for disease-free survival. Lymphovascular space invasion was associated significantly with early tumor recurrence but not with overall survival. Conclusions: Vascular and lymphatic invasion can serve as independent prognostic factors in completely resected nonsmall- cell lung cancer. Intratumoral vascular invasion and lymphovascular space invasion in early stage non-small-cell lung cancer are important factors in overall survival and early tumor recurrence. Further large scale studies with more recent patient cohorts and refined histological techniques are warranted.

Genome stability pathways in head and neck cancers

Genomic instability underlies the transformation of host cells toward malignancy, promotes development of invasion and metastasis and shapes the response of established cancer to treatment. In this review, we discuss recent advances in our understanding of genomic stability in squamous cell carcinoma of the head and neck (HNSCC), with an emphasis on DNA repair pathways. HNSCC is characterized by distinct profiles in genome stability between similarly staged cancers that are reflected in risk, treatment response and outcomes. Defective DNA repair generates chromosomal derangement that can cause subsequent alterations in gene expression, and is a hallmark of progression toward carcinoma. Variable functionality of an increasing spectrum of repair gene polymorphisms is associated with increased cancer risk, while aetiological factors such as human papillomavirus, tobacco and alcohol induce significantly different behaviour in induced malignancy, underpinned by differences in genomic stability. Targeted inhibition of signalling receptors has proven to be a clinically-validated therapy, and protein expression of other DNA repair and signalling molecules associated with cancer behaviour could potentially provide a more refined clinical model for prognosis and treatment prediction. Development and expansion of current genomic stability models is furthering our understanding of HNSCC pathophysiology and uncovering new, promising treatment strategies. © 2013 Glenn Jenkins et al.

Acquired differential regulation of caspase-8 in cisplatin-resistant non-small-cell lung cancer

Failure to efficiently induce apoptosis contributes to cisplatin resistance in non-small-cell lung cancer (NSCLC). Although BCL-2-associated X protein (BAX) and BCL-2 antagonist killer (BAK) are critical regulators of the mitochondrial apoptosis pathway, their requirement has not been robustly established in relation to cisplatin. Here, we show that cisplatin can efficiently bypass mitochondrial apoptosis block caused by loss of BAX and BAK, via activation of the extrinsic death receptor pathway in some model cell lines. Apoptosis resistance following cisplatin can only be observed when both extrinsic and intrinsic pathways are blocked, consistent with redundancy between mitochondrial and death receptor pathways in cisplatin-induced apoptosis. In H460 NSCLC cells, caspase-8 cleavage was shown to be induced by cisplatin and is dependent on death receptor 4, death receptor 5, Fas-associated protein with death domain, acid sphingomyelinase and ceramide synthesis. In contrast, cisplatin-resistant cells fail to activate caspase-8 via this pathway despite conserving sensitivity to death ligand-driven activation. Accordingly, caspase-8 activation block acquired during cisplatin resistance, can be bypassed by death receptor agonism.

Symptom control and quality of life in lux-lung 3 : a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations

Purpose Patient-reported symptoms and health-related quality of life (QoL) benefits were investigated in a randomized, phase III trial of afatinib or cisplatin/pemetrexed. Patients and Methods Three hundred forty-five patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma were randomly assigned 2:1 to afatinib 40 mg per day or up to six cycles of cisplatin/pemetrexed. Lung cancer symptoms and health-related QoL were assessed every 21 days until progression using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 questionnaires. Analyses of cough, dyspnea, and pain were preplanned, including percentage of patients who improved on therapy, time to deterioration of symptoms, and change in symptoms over time. Results Questionnaire compliance was high. Compared with chemotherapy, afatinib significantly delayed the time to deterioration for cough (hazard ratio [HR], 0.60; 95% CI, 0.41 to 0.87; P = .007) and dyspnea (HR, 0.68; 95% CI, 0.50 to 0.93; P = .015), but not pain (HR, 0.83; 95% CI, 0.62 to 1.10; P = .19). More patients on afatinib (64%) versus chemotherapy (50%) experienced improvements in dyspnea scores (P lt; .010). Differences in mean scores over time significantly favored afatinib over chemotherapy for cough (P lt; .001) and dyspnea (P = .001). Afatinib showed significantly better mean scores over time in global health status/QoL (P = .015) and physical (P = .001), role (P = .004), and cognitive (P lt; .007) functioning compared with chemotherapy. Fatigue and nausea were worse with chemotherapy, whereas diarrhea, dysphagia, and sore mouth were worse with afatinib (all P = .01). Conclusion In patients with lung adenocarcinoma with EGFR mutations, first-line afatinib was associated with better control of cough and dyspnea compared with chemotherapy, although diarrhea, dysphagia, and sore mouth were worse. Global health status/QoL was also improved over time with afatinib compared with chemotherapy.

Elucidating the host–pathogen interaction between human colorectal cells and invading Enterovirus 71 using transcriptomics profiling

Enterovirus 71 (EV71) is one of the main etiological agents for Hand, Foot and Mouth Disease (HFMD) and has been shown to be associated with severe clinical manifestation. Currently, there is no antiviral therapeutic for the treatment of HFMD patients owing to a lack of understanding of EV71 pathogenesis. This study seeks to elucidate the transcriptomic changes that result from EV71 infection. Human whole genome microarray was employed to monitor changes in genomic profiles between infected and uninfected cells. The results reveal altered expression of human genes involved in critical pathways including the immune response and the stress response. Together, data from this study provide valuable insights into the host–pathogen interaction between human colorectal cells and EV71.

Enterovirus71 (EV71) utilise host microRNAs to mediate host immune system enhancing survival during infection

Hand, Foot and Mouth Disease (HFMD) is a self-limiting viral disease that mainly affects infants and children. In contrast with other HFMD causing enteroviruses, Enterovirus71 (EV71) has commonly been associated with severe clinical manifestation leading to death. Currently, due to a lack in understanding of EV71 pathogenesis, there is no antiviral therapeutics for the treatment of HFMD patients. Therefore the need to better understand the mechanism of EV71 pathogenesis is warranted. We have previously reported a human colorectal adenocarcinoma cell line (HT29) based model to study the pathogenesis of EV71. Using this system, we showed that knockdown of DGCR8, an essential cofactor for microRNAs biogenesis resulted in a reduction of EV71 replication. We also demonstrated that there are miRNAs changes during EV71 pathogenesis and EV71 utilise host miRNAs to attenuate antiviral pathways during infection. Together, data from this study provide critical information on the role of miRNAs during EV71 infection.

Aha! The return of Alan Partridge

Throughout a long and occasionally distinguished career first as a television sports correspondent, then chat show host (dramatically ended by the accidental homicide of a guest live on air), then rebirth as a radio presenter at North Norfolk Digital, Alan Partridge has navigated the stormy waters of the British media landscape, now achieving mainstream success on the big screen with a starring role in Steve Coogan’s Alpha Papa (Declan Lowney, 2013). A man who in his desperation for a television series of his own once sank so low as to pitch a show called Monkey Tennis to the BBC finally finds his inner hero in a film which, while presenting mainly as comedy, also contains a biting critique of trends in the British media with which all journalists and media practitioners in general will be familiar. Alpha Papa is a nostalgic, elegiac riff on the pleasures and values of local radio the way it used to be, exemplified by North Norfolk Digital’s stable of flawed, but endearing jocks – Wally Banter, Bruno Brooks, Dave Clifton (who in one scene recounts the depths to which he sank as an alcoholic, drug addicted wreck—“I woke up in a skip with someone else’s underpants in my mouth. I can laugh about it now …”), and Pat Farrell. 50- something Pat is sacked by the new owners of North Norfolk Digital, who in their efforts to transform the station into a “multiplatform content provider” going by the more Gen Yfriendly name of Shape (“the way you want it to be”), wish to replace him with a younger, brattish model lacking in taste and manners. Out go records by the likes of Glen Campbell and Neil Diamond (“You can keep Jesus Christ”, observes Partridge after playing Diamond’s Sweet Caroline in a demonstration of the crackling radio repartee for which he is by now renowned, “that was the king of the Jews”), in comes Roachford. Pat, grieving his dead wife Molly, finally snaps and turns the glitzy media launch of Shape into a hostage siege. Only Alan Partridge, it seems, can step in and talk Pat out of a looming catastrophe.

Human exposure to brominated flame retardants

Human polybrominated diphenyl ether (PBDE) exposure occurs through a range of pathways including: ingestion of dust including hand-to-mouth contact; inhalation (air/particulate matter); and ingestion via food including the unique nutrition sources of human milk and placental transfer. While inhalation has been deemed a minor source of exposure, ingestion of food and dust make greater contributions to overall PBDE body burden with intake via dust reported to be much higher in infants than in adults. PBDEs have been detected in samples of human milk, blood serum, cord blood, and adipose tissue worldwide. Concentrations have been found to be highest in populations from North America, followed by Australia, Europe, and Asia. While factors such as gender and parity may not affect concentrations, occupational exposure and age (infants and children) are associated with higher PBDE concentrations. In contrast to “traditional” persistent organic pollutants, there is an inverse relationship between PBDE body burden and age. Predicted body burden calculated using available information on intake and elimination rates of BFRs appears to underestimate measured human body burden data obtained through analysis of BFRs in blood or human milk. This may be due to unknown exposure or inaccurate elimination data. Further exposure studies should focus on younger age groups and an investigation of human PBDE half-lives.

Educational programmes for primary prevention of skin cancer (Protocol)

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of education programmes for skin cancer prevention in the general population. Description of the condition Skin cancer is a term that includes both melanoma and keratinocyte cancer. Keratinocyte cancer (also known as nonmelanoma skin cancer) generally refers to basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), although it also includes other rare cutaneous neoplasms (Madan 2010). Skin cancer is the most common cancer in populations of predominantly fair-skinned people (Donaldson 2011; Lomas 2012; Stern 2010), with incidence increasing (Garbe 2009; Leiter 2012). There are variations in annual incidence rates between these populations, with Australia reporting the highest rate of skin cancer in the world (Lomas 2012). In 2012, the estimated age-standardised incidence rate for melanoma was almost 63 per 100,000 people for Australian men, and 40 per 100,000 people for Australian women (AIHW 2012). In Europe, incidence rates range from 10 to 15 per 100,000 people (Garbe 2009; Lasithiotakis 2006), with rates highest amongst men (Stang 2006). In the United States, incidence rates are approximately 18 per 100,000 people (Garbe 2009),with the highest rates reported forwomen (Bradford 2010). Keratinocyte cancer is much more common than melanoma. In 2012, the estimated Australian age-standardised rates for BCCand SCC were 884 and 387 per 100,000 people, respectively (Staples 2006). The cumulative three-year risk of developing a subsequent keratinocyte cancer is 18% for SCC and 44% for BCC (Marcil 2000).

Random Gabor based templates for facial expression recognition in images with facial occlusion

Robust facial expression recognition (FER) under occluded face conditions is challenging. It requires robust algorithms of feature extraction and investigations into the effects of different types of occlusion on the recognition performance to gain insight. Previous FER studies in this area have been limited. They have spanned recovery strategies for loss of local texture information and testing limited to only a few types of occlusion and predominantly a matched train-test strategy. This paper proposes a robust approach that employs a Monte Carlo algorithm to extract a set of Gabor based part-face templates from gallery images and converts these templates into template match distance features. The resulting feature vectors are robust to occlusion because occluded parts are covered by some but not all of the random templates. The method is evaluated using facial images with occluded regions around the eyes and the mouth, randomly placed occlusion patches of different sizes, and near-realistic occlusion of eyes with clear and solid glasses. Both matched and mis-matched train and test strategies are adopted to analyze the effects of such occlusion. Overall recognition performance and the performance for each facial expression are investigated. Experimental results on the Cohn-Kanade and JAFFE databases demonstrate the high robustness and fast processing speed of our approach, and provide useful insight into the effects of occlusion on FER. The results on the parameter sensitivity demonstrate a certain level of robustness of the approach to changes in the orientation and scale of Gabor filters, the size of templates, and occlusions ratios. Performance comparisons with previous approaches show that the proposed method is more robust to occlusion with lower reductions in accuracy from occlusion of eyes or mouth.

Securing medical devices Part A : what’s available for endotracheal tubes?

Oral endotracheal tubes (ETTs) and nasogastric tubes (NGT) are common devices used in adult intensive care and numerous options exist for safe and comfortable securement of these devices. The aim of this project was to identify the available range of ETT and NGT securement devices in Australia as a resource for clinicians seeking to explore options for tube stabilisation. This article reports part A of this project: ETT securement options. Part B will report NGT device fixation options. Securing ETTs to ensure a patent airway with minimal ETT movement, promotion of patient comfort and absence of adverse events such as ETT dislodgement, unplanned extubation and device-related injury1, are essential critical care nursing actions. The ETT requires a fixation method that is robust yet does not traumatise or injure the mucosal tissues of the mouth and soft tissue of the lips.2,3 Choice of a securement apparatus is often determined by product availability in our units or hospitals but is also driven by evidence-based practice and clinician preference. Trying to put this information together can be difficult and time-consuming for the bedside clinician...

Mothers influencing mothers : the use of virtual discussion boards and their influence on consumption

Mothers represent a large segment of marketing dollars and traditionally, word of mouth was spread from mother to mother in a face-to-face environment, such as the school car park or mother’s groups. As families have evolved, so too has the traditional mother’s group. Limited academic studies have explored online mothers’ groups and how they impact on consumption. In order to explore the nature of this online influence and how mothers are influenced by other mothers online, a study was conducted through the use of observation and qualitative questioning. The data suggests that trust between mothers is generally high and mothers tend to trust the opinions of other mothers when they recommend a product. This is similar in other reference group contexts, however, mothers are communicating about brands frequently and influencing behaviour. This leads to a number of managerial and theoretical implications discussed in the paper.

Vimentin expression in cervical carcinomas : association with invasive and migratory potential

Vimentin is an intermediate filament protein normally expressed in mesenchymal cells, but evidence is accumulating in the literature which suggests that the aberrant expression of vimentin in epithelial cancer cells might be related to local invasiveness and metastatic potential. Vimentin expression has previously been associated with invasive properties in an in vitro model consisting of a set of HPV-33-transformed cervical keratinocyte cell lines. In the present study, in order to emphasize those in vitro findings, the expression of vimentin has been investigated in cervical neoplasms of different grades, using immunohistochemistry. A clear association is reported between vimentin expression and metastatic progression, since vimentin was detected in all invasive carcinomas and lymph node metastases, but not in CIN III lesions. These in vivo results are compared with present and previous data obtained in vitro on cervical keratinocyte cell lines, where vimentin expression also correlated with in vitro invasiveness.

The effect of the histological properties of tumors on transfection efficiency of electrically assisted gene delivery to solid tumors in mice

Uniform DNA distribution in tumors is a prerequisite step for high transfection efficiency in solid tumors. To improve the transfection efficiency of electrically assisted gene delivery to solid tumors in vivo, we explored how tumor histological properties affected transfection efficiency. In four different tumor types (B16F1, EAT, SA-1 and LPB), proteoglycan and collagen content was morphometrically analyzed, and cell size and cell density were determined in paraffin-embedded tumor sections under a transmission microscope. To demonstrate the influence of the histological properties of solid tumors on electrically assisted gene delivery, the correlation between histological properties and transfection efficiency with regard to the time interval between DNA injection and electroporation was determined. Our data demonstrate that soft tumors with larger spherical cells, low proteoglycan and collagen content, and low cell density are more effectively transfected (B16F1 and EAT) than rigid tumors with high proteoglycan and collagen content, small spindle-shaped cells and high cell density (LPB and SA-1). Furthermore, an optimal time interval for increased transfection exists only in soft tumors, this being in the range of 5-15 min. Therefore, knowledge about the histology of tumors is important in planning electrogene therapy with respect to the time interval between DNA injection and electroporation.

Controlled systemic release of interleukin-12 after gene electrotransfer to muscle for cancer gene therapy alone or in combination with ionizing radiation in murine sarcomas

Background: The present study aimed to evaluate the antitumor effectiveness of systemic interleukin (IL)-12 gene therapy in murine sarcoma models, and to evaluate its interaction with the irradiation of tumors and metastases. To avoid toxic side-effects of IL-12 gene therapy, the objective was to achieve the controlled release of IL-12 after intramuscular gene electrotransfer. Methods: Gene electrotransfer of the plasmid pORF-mIL12 was performed into the tibialis cranialis in A/J and C57BL/6 mice. Systemic release of the IL-12 was monitored in the serum of mice after carrying out two sets of intramuscular IL-12 gene electrotransfer of two different doses of plasmid DNA. The antitumor effectiveness of IL-12 gene electrotransfer alone or in combination with local tumor or lung irradiation with X-rays, was evaluated on subcutaneous SA-1 and LPB tumors, as well as on lung metastases. Results: A synergistic antitumor effect of intramuscular gene electrotransfer combined with local tumor irradiation was observed as a result of the systemic distribution of IL-12. The gene electrotransfer resulted in up to 28% of complete responses of tumors. In combination with local tumor irradiation, the curability was increased by up to 100%. The same effect was observed for lung metastases, where a potentiating factor of 1.3-fold was determined. The amount of circulating IL-12 was controlled by the number of repeats of gene electrotransfer and by the amount of the injected plasmid. Conclusions: The present study demonstrates the feasibility of treatment by IL-12 gene electrotransfer combined with local tumor or lung metastases irradiation on sarcoma tumors for translation into the clinical setting. Copyright © 2009 John Wiley & Sons, Ltd.