Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment : the M77001 study group

Purpose: This randomized, multicenter trial compared first-line trastuzumab plus docetaxel versus docetaxel alone in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Patients and Methods: Patients were randomly assigned to six cycles of docetaxel 100 mg/m 2 every 3 weeks, with or without trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly until disease progression. Results: A total of 186 patients received at least one dose of the study drug. Trastuzumab plus docetaxel was significantly superior to docetaxel alone in terms of overall response rate (61% v 34%; P = .0002), overall survival (median, 31.2 v 22.7 months; P = .0325), time to disease progression (median, 11.7 v 6.1 months; P = .0001), time to treatment failure (median, 9.8 v 5.3 months; P = .0001), and duration of response (median, 11.7 v 5.7 months; P = .009). There was little difference in the number and severity of adverse events between the arms. Grade 3 to 4 neutropenia was seen more commonly with the combination (32%) than with docetaxel alone (22%), and there was a slightly higher incidence of febrile neutropenia in the combination arm (23% v 17%). One patient in the combination arm experienced symptomatic heart failure (1%). Another patient experienced symptomatic heart failure 5 months after discontinuation of trastuzumab because of disease progression, while being treated with an investigational anthracycline for 4 months. Conclusion: Trastuzumab combined with docetaxel is superior to docetaxel alone as first-line treatment of patients with HER2-positive MBC in terms of overall survival, response rate, response duration, time to progression, and time to treatment failure, with little additional toxicity. © 2005 by American Society of Clinical Oncology.

A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer

The aims of this phase I study were to establish the maximum tolerated dose, safety profile and activity of liposomal daunorubicin, DaunoXome (NeXstar Pharmaceuticals), in the treatment of metastatic breast cancer. DaunoXome was administered intravenously over 2 h in 21 day cycles and doses were increased from 80 to 100, 120 and 150 mg m 2. Sixteen patients were enrolled. A total of 70 cycles of DaunoXome were administered. The maximum tolerated dose was 120 mg m 2, the dose-limiting toxicity being prolonged grade 4 neutropenia or neutropenic pyrexia necessitating dose reductions at 120 and 150 mg m 2. Asymptomatic cardiotoxicity was observed in three patients: grade 1 in one treated with a cumulative dose of 800 mg m 2 and grade 2 in two, one who received a cumulative dose of 960 mg m 2 and the other a cumulative dose of 600 mg m 2 with a previous neoadjuvant doxorubicin chemotherapy of 300 mg m 2. Tumour response was evaluable in 15 patients, of whom two had objective responses, six had stable disease and seven had progressive disease. In conclusion, DaunoXome is associated with mild, manageable toxicities and has anti-tumour activity in metastatic breast cancer. The findings support further phase II evaluation of DaunoXome alone and in combination with other standard non-anthracycline cytotoxic or novel targeted agents. Although the dose-limiting toxicity for DaunoXome was febrile neutropenia at 120 mg m 2, we would recommend this dose for further evaluation, as the febrile neutropenia occurred after four or more cycles in three of the four episodes seen, was short lived and uncomplicated. © 2002 Cancer Research UK.

Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX) : an open-label randomised phase III trial

Background: Use of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has the potential to increase survival in patients with advanced non-small-cell lung cancer. We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer. Methods: In a multinational, multicentre, open-label, phase III trial, chemotherapy-naive patients (≥18 years) with advanced EGFR-expressing histologically or cytologically proven stage wet IIIB or stage IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio to chemotherapy plus cetuximab or just chemotherapy. Chemotherapy was cisplatin 80 mg/m 2 intravenous infusion on day 1, and vinorelbine 25 mg/m 2 intravenous infusion on days 1 and 8 of every 3-week cycle) for up to six cycles. Cetuximab-at a starting dose of 400 mg/m 2 intravenous infusion over 2 h on day 1, and from day 8 onwards at 250 mg/m 2 over 1 h per week-was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred. The primary endpoint was overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00148798. Findings: Between October, 2004, and January, 2006, 1125 patients were randomly assigned to chemotherapy plus cetuximab (n=557) or chemotherapy alone (n=568). Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median 11·3 months vs 10·1 months; hazard ratio for death 0·871 [95% CI 0·762-0·996]; p=0·044). The main cetuximab-related adverse event was acne-like rash (57 [10%] of 548, grade 3). Interpretation: Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer. Funding: Merck KGaA. © 2009 Elsevier Ltd. All rights reserved.

Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer

Background: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics. Patients and methods: Following randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m2, day 1) and vinorelbine (25 mg/m2 on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m, followed by 250 mg/m2 weekly thereafter). Results: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated. Conclusion: In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone. © 2007 European Society for Medical Oncology.

Management of endocrine resistant breast cancer

Metastatic breast cancer (MBC) may present de novo but more commonly develops in women initially presenting with early breast cancer despite the widespread use of adjuvant hormonal and cytotoxic chemotherapy. MBC is incurable. Hormone sensitive MBC eventually becomes resistant to endocrine therapy in most women. Anthracyclines are the agents of choice in the treatment of endocrine resistant MBC. With the widespread use of anthracyclines in the adjuvant setting, taxanes have become the agents of choice for many patients. Recently capecitabine has become established as a standard of care for patients pretreated with anthracyclines and taxanes. However, a range of agents have activity as third line treatment. These include gemcitabine, vinorelbine and platinum analogues. The sequential use of non-cross resistant single agents rather than combination therapy is preferable in most women with MBC. Even though combination therapy can improve response rates and increase progression free interval, there is no robust evidence to indicate an advantage in terms of overall survival. Moreover, combination therapy is associated with a higher toxicity rate and poor quality of life. There is no role for dose-intense therapy, high dose therapy or maintenance chemotherapy outside the context of a clinical trial. The introduction of trastuzumab, monoclonal antibody targeting growth factor receptors, has improved the therapeutic options for women with tumours overexpressing HER2/neu. DNA micro-array profiles of tumours can potentially help to individualise therapy in future. Molecular targeted therapy has the potential to revolutionise the management of MBC.

Chemotherapy for upper gastrointestinal tumours

The aim of this review is to identify current chemotherapy treatment for tumours of the oesophagus, stomach, pancreas, and liver. The role of both neoadjuvant, adjuvant, and palliative chemotherapy regimens will be discussed. This review will be of interest to oncologists in clarifying current issues regarding chemotherapy, and to physicians in other medical specialties, to increase their general understanding of benefits and drawbacks of chemotherapy in this patient group.

Plain facts about pleading : how to work with r 166

The decision of Durward SC DCJ in OSM Group Pty Ltd v Holden [2013] QDC 151 involves a useful consideration of the requirements relating to the pleading of denials and non-admissions under the Uniform Civil Procedure Rules 1999 (Qld) (UCPR). In particular, the decision examines the extent of the obligations when pleading in response to allegations of law, or of mixed fact and law.

Examining the impact of climate change on dengue transmission in the Asia-Pacific region

Dengue fever (DF) is a serious public health concern in many parts of the world. An increase in DF incidence has been observed globally over the past decades. Multiple factors including urbanisation, increased international travels and global climate change are thought to be responsible for increased DF. However, little research has been conducted in the Asia-Pacific region about the impact of these changes on dengue transmission. The overarching aim of this thesis is to explore the spatiotemporal pattern of DF transmission in the Asia-Pacific region and project the future risk of DF attributable to climate change. Annual data of DF outbreaks for sixteen countries in the Asia-Pacific region over the last fifty years were used in this study. The results show that the geographic range of DF in this region increased significantly over the study period. Thailand, Vietnam and Laos were identified as the highest risk areas and there was a southward expansion observed in the transmission pattern of DF which might have originated from Philippines or Thailand. Additionally, the detailed DF data were obtained and the space-time clustering of DF transmission was examined in Bangladesh. Monthly DF data were used for the entire country at the district level during 2000-2009. Dhaka district was identified as the most likely DF cluster in Bangladesh and several districts of the southern part of Bangladesh were identified as secondary clusters in the years 2000-2002. In order to examine the association between meteorological factors and DF transmission and to project the future risk of DF using different climate change scenarios, the climate-DF relationship was examined in Dhaka, Bangladesh. The results show that climate variability (particularly maximum temperature and relative humidity) was positively associated with DF transmission in Dhaka. The effects of climate variability were observed at a lag of four months which might help to potentially control and prevent DF outbreaks through effective vector management and community education. Based on the quantitative assessment of the climate-DF relationship, projected climate change will likely increase mosquito abundance and activity and DF in this area. Assuming a temperature increase of 3.3oC without any adaptation measures and significant changes in socio-economic conditions, the consequence will be devastating, with a projected annual increase of 16,030 cases in Dhaka, Bangladesh by the end of this century. Therefore, public health authorities need to be prepared for likely increase of DF transmission in this region. This study adds to the literature on the recent trends of DF and impacts of climate change on DF transmission. These findings may have significant public health implications for the control and prevention of DF, particularly in the Asia- Pacific region.

Slicing big data - Twitter, gambling and time sensitive information

Big Data presents many challenges related to volume, whether one is interested in studying past datasets or, even more problematically, attempting to work with live streams of data. The most obvious challenge, in a ‘noisy’ environment such as contemporary social media, is to collect the pertinent information; be that information for a specific study, tweets which can inform emergency services or other responders to an ongoing crisis, or give an advantage to those involved in prediction markets. Often, such a process is iterative, with keywords and hashtags changing with the passage of time, and both collection and analytic methodologies need to be continually adapted to respond to this changing information. While many of the data sets collected and analyzed are preformed, that is they are built around a particular keyword, hashtag, or set of authors, they still contain a large volume of information, much of which is unnecessary for the current purpose and/or potentially useful for future projects. Accordingly, this panel considers methods for separating and combining data to optimize big data research and report findings to stakeholders. The first paper considers possible coding mechanisms for incoming tweets during a crisis, taking a large stream of incoming tweets and selecting which of those need to be immediately placed in front of responders, for manual filtering and possible action. The paper suggests two solutions for this, content analysis and user profiling. In the former case, aspects of the tweet are assigned a score to assess its likely relationship to the topic at hand, and the urgency of the information, whilst the latter attempts to identify those users who are either serving as amplifiers of information or are known as an authoritative source. Through these techniques, the information contained in a large dataset could be filtered down to match the expected capacity of emergency responders, and knowledge as to the core keywords or hashtags relating to the current event is constantly refined for future data collection. The second paper is also concerned with identifying significant tweets, but in this case tweets relevant to particular prediction market; tennis betting. As increasing numbers of professional sports men and women create Twitter accounts to communicate with their fans, information is being shared regarding injuries, form and emotions which have the potential to impact on future results. As has already been demonstrated with leading US sports, such information is extremely valuable. Tennis, as with American Football (NFL) and Baseball (MLB) has paid subscription services which manually filter incoming news sources, including tweets, for information valuable to gamblers, gambling operators, and fantasy sports players. However, whilst such services are still niche operations, much of the value of information is lost by the time it reaches one of these services. The paper thus considers how information could be filtered from twitter user lists and hash tag or keyword monitoring, assessing the value of the source, information, and the prediction markets to which it may relate. The third paper examines methods for collecting Twitter data and following changes in an ongoing, dynamic social movement, such as the Occupy Wall Street movement. It involves the development of technical infrastructure to collect and make the tweets available for exploration and analysis. A strategy to respond to changes in the social movement is also required or the resulting tweets will only reflect the discussions and strategies the movement used at the time the keyword list is created — in a way, keyword creation is part strategy and part art. In this paper we describe strategies for the creation of a social media archive, specifically tweets related to the Occupy Wall Street movement, and methods for continuing to adapt data collection strategies as the movement’s presence in Twitter changes over time. We also discuss the opportunities and methods to extract data smaller slices of data from an archive of social media data to support a multitude of research projects in multiple fields of study. The common theme amongst these papers is that of constructing a data set, filtering it for a specific purpose, and then using the resulting information to aid in future data collection. The intention is that through the papers presented, and subsequent discussion, the panel will inform the wider research community not only on the objectives and limitations of data collection, live analytics, and filtering, but also on current and in-development methodologies that could be adopted by those working with such datasets, and how such approaches could be customized depending on the project stakeholders.

Detouring to Grafton : the Sydney Botanic Gardens and the making of an Australian urban aesthetic

For the last seventy-five years Grafton has celebrated the Jacaranda Festival in late October. The festival commences in the town square with the crowning of the Jacaranda Queen and ends a week later with a parade through the town. The event is now a major regional tourist attraction that aims to bring locals and visitors together to celebrate everything purple. During this week one can attend the jacaranda children's party, the jacaranda maypole dancing, the jacaranda choral service or the jacaranda organ recital. Local businesses are encouraged to compete in the decorated window displays competition and everyone can join in the procession. The festival pays homage to the extraordinary display of beautiful jacaranda blooms which carpet the city during this time. The festival was inaugurated in 1935 when the slow growing jacarandas planted in the late nineteenth and early twentieth centuries were coming to maturity...

A threshold analysis of dengue transmission in terms of weather variables and imported dengue cases in Australia

Dengue virus (DENV) transmission in Australia is driven by weather factors and imported dengue fever (DF) cases. However, uncertainty remains regarding the threshold effects of high-order interactions among weather factors and imported DF cases and the impact of these factors on autochthonous DF. A time-series regression tree model was used to assess the threshold effects of natural temporal variations of weekly weather factors and weekly imported DF cases in relation to incidence of weekly autochthonous DF from 1 January 2000 to 31 December 2009 in Townsville and Cairns, Australia. In Cairns, mean weekly autochthonous DF incidence increased 16.3-fold when the 3-week lagged moving average maximum temperature was <32 °C, the 4-week lagged moving average minimum temperature was ≥24 °C and the sum of imported DF cases in the previous 2 weeks was >0. When the 3-week lagged moving average maximum temperature was ≥32 °C and the other two conditions mentioned above remained the same, mean weekly autochthonous DF incidence only increased 4.6-fold. In Townsville, the mean weekly incidence of autochthonous DF increased 10-fold when 3-week lagged moving average rainfall was ≥27 mm, but it only increased 1.8-fold when rainfall was <27 mm during January to June. Thus, we found different responses of autochthonous DF incidence to weather factors and imported DF cases in Townsville and Cairns. Imported DF cases may also trigger and enhance local outbreaks under favorable climate conditions.

Imported Dengue cases, weather variation and autochthonous Dengue incidence in Cairns, Australia

BACKGROUND Dengue fever (DF) outbreaks often arise from imported DF cases in Cairns, Australia. Few studies have incorporated imported DF cases in the estimation of the relationship between weather variability and incidence of autochthonous DF. The study aimed to examine the impact of weather variability on autochthonous DF infection after accounting for imported DF cases and then to explore the possibility of developing an empirical forecast system. METHODOLOGY/PRINCIPAL FINDS Data on weather variables, notified DF cases (including those acquired locally and overseas), and population size in Cairns were supplied by the Australian Bureau of Meteorology, Queensland Health, and Australian Bureau of Statistics. A time-series negative-binomial hurdle model was used to assess the effects of imported DF cases and weather variability on autochthonous DF incidence. Our results showed that monthly autochthonous DF incidences were significantly associated with monthly imported DF cases (Relative Risk (RR):1.52; 95% confidence interval (CI): 1.01-2.28), monthly minimum temperature ((o)C) (RR: 2.28; 95% CI: 1.77-2.93), monthly relative humidity (%) (RR: 1.21; 95% CI: 1.06-1.37), monthly rainfall (mm) (RR: 0.50; 95% CI: 0.31-0.81) and monthly standard deviation of daily relative humidity (%) (RR: 1.27; 95% CI: 1.08-1.50). In the zero hurdle component, the occurrence of monthly autochthonous DF cases was significantly associated with monthly minimum temperature (Odds Ratio (OR): 1.64; 95% CI: 1.01-2.67). CONCLUSIONS/SIGNIFICANCE Our research suggested that incidences of monthly autochthonous DF were strongly positively associated with monthly imported DF cases, local minimum temperature and inter-month relative humidity variability in Cairns. Moreover, DF outbreak in Cairns was driven by imported DF cases only under favourable seasons and weather conditions in the study.

QUT Architecture Film Studio (Aus)

Research Statement: An urban film produced by Luke Harrison Mitchell Benham, Sharlene Anderson, Tristan Clark. RIVE NOIR explores the film noir tradition, shot on location in a dark urban space between high-rises and the river, sheltered by a highway. With an original score and striking cinematography, Rive Noir radically transforms the abandoned river’s edge through the production of an amplified reality ordinarily unseen in the Northbank. The work produced under my supervision was selected to appear in the Expanded Architecture Research Group’s International Architecture Film Festival and Panel Discussion in Sydney: The University of Sydney and Carriageworks Performance Space, 06 November 2011. QUT School of Design research submission was selected alongside exhibits by AA School of Architecture, London; The Bartlett School of Architecture, London; University of The Arts, London; Arrhaus School of Architecture, Denmark; Dublin as a Cinematic City, Ireland; Design Lab Screen Studio, Australia; and Sona Cinecity, The University of Melbourne. The exhibit included not only the screening of the film but the design project that derived from and extended the aesthetics of the urban film. The urban proposal and architectural intervention that followed the film was subsequently published in the Brisbane Times, after the urban proposal won first place in The Future of Brisbane architecture competition, which demonstrates the impact of the research project as a whole. EXPANDED ARCHITECTURE 2011 - 6th November Architecture Film Night + Panel Discussion @ Performance Space CarriageWorks was Sydney's first International Architectural Film Festival. With over 40 architectural films by local and international artists, film makers and architects. It was followed by Panel Discussion of esteemed academics and artists working in the field of architectural film.

Selection et controle de modes de deplacement pour un robot mobile autonome en environnements naturels

Autonomous navigation and locomotion of a mobile robot in natural environments remain a rather open issue. Several functionalities are required to complete the usual perception/decision/action cycle. They can be divided in two main categories : navigation (perception and decision about the movement) and locomotion (movement execution). In order to be able to face the large range of possible situations in natural environments, it is essential to make use of various kinds of complementary functionalities, defining various navigation and locomotion modes. Indeed, a number of navigation and locomotion approaches have been proposed in the literature for the last years, but none can pretend being able to achieve autonomous navigation and locomotion in every situation. Thus, it seems relevant to endow an outdoor mobile robot with several complementary navigation and locomotion modes. Accordingly, the robot must also have means to select the most appropriate mode to apply. This thesis proposes the development of such a navigation/locomotion mode selection system, based on two types of data: an observation of the context to determine in what kind of situation the robot has to achieve its movement and an evaluation of the behavior of the current mode, made by monitors which influence the transitions towards other modes when the behavior of the current one is considered as non satisfying. Hence, this document introduces a probabilistic framework for the estimation of the mode to be applied, some navigation and locomotion modes used, a qualitative terrain representation method (based on the evaluation of a difficulty computed from the placement of the robot's structure on a digital elevation map), and monitors that check the behavior of the modes used (evaluation of rolling locomotion efficiency, robot's attitude and configuration watching. . .). Some experimental results obtained with those elements integrated on board two different outdoor robots are presented and discussed.