Platinum-based chemotherapy in metastatic breast cancer : the Leicester (UK) experience

Aims: After failure of anthracycline- and taxane-based chemotherapy in metastatic breast cancer, treatment options until recently were limited. Until the introduction of capecitabine and vinorelbine, no standard regimen was available. We conducted a retrospective study to determine the efficacy and toxicity of platinum-based chemotherapy in metastatic breast cancer. Materials and methods: Forty-two women with metastatic breast cancer previously treated with anthracyclines (93%) and/or taxanes (36%) received mitomycin-vinblastine-cisplatin (MVP) (n = 23), or cisplatin-etoposide (PE) (n = 19), as first-, second- and third-line treatment at a tertiary referral centre between 1997 and 2002. Chemotherapy was given every 3 weeks as follows: mitomycin-C (8 mg/m 2) (cycles 1, 2, 4, 6), vinblastine (6 mg/m 2), and cisplatin (50 mg/m 2) all on day 1; and cisplatin (75 mg/m 2) and etoposide (100 mg/m 2) on day 1 and (100 mg/m 2) orally twice a day on days 2-3. Results: The response rate for 40 evaluable patients (MVP: n = 23; PE: n = 17) was 18% (95% confidence interval [CI]: 9-32%). The response rate to MVP was 13% (95% CI: 5-32%, one complete and two partial responses) and to PE 24% (10-47%, four partial responses). Disease stabilised in 43% (26-63%) and 47% (26-69%) of women treated with MVP and PE, respectively. After a median follow-up of 18 months, 37 women (MVP: n = 19; PE: n = 18) died from their disease. Median (range) progression-free survival and overall survival were 6 months (0.4-18.7) and 9.9 months (1.3-40.8), respectively. Median progression-free survival for the MVP and PE groups was 5.5 and 6.2 months (Log-rank, P = 0.82), and median overall survival was 10.2 and 9.4 months (Log-rank, P = 0.46), respectively. The main toxicity was myelosuppression. Grades 3-4 neutropenia was more common in women treated with PE than in women treated with MVP (74% vs 30%; P = 0.012), but the incidence of neutropenic sepsis, relative to the number of chemotherapy cycles, was low (7% overall). The toxicity-related hospitalisation rate was 1.2 admissions per six cycles of chemotherapy. No treatment-related deaths occurred. MVP and PE chemotherapy have modest activity and are safe in women with metastatic breast cancer. © 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Advances in the systemic therapy of malignant pleural mesothelioma

Malignant pleural mesothelioma is an aggressive thoracic malignancy associated with exposure to asbestos, and its incidence is anticipated to increase during the first half of this century. Chemotherapy is the mainstay of treatment, yet sufficiently robust evidence to substantiate the current standard of care has emerged only in the past 5 years. This Review summarizes the evidence supporting the clinical activity of chemotherapy, discusses the use of end points for its assessment and examines the influence of clinical and biochemical prognostic factors on the natural history of malignant pleural mesothelioma. Early-phase clinical trials of second-line and novel agents are emerging from an increased understanding of mesothelioma cell biology. Coupled with high-quality translational research, such developments have real potential to improve the outlook of patients at a time of increasing incidence.

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.

Antibody treatments of inflammatory arthritis

Inflammatory arthropathies such as rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis are extremely common in the community, with a prevalence of up to 5%, and they cause substantial morbidity. The development of anti-TNF agents for use initially in rheumatoid arthritis, and subsequently more broadly in inflammatory arthritis, represents the biggest advance in management of these conditions since the introduction of corticosteroid agents, and is a major vindication of public funded arthritis research. However, there are limitations of even these highly effective agents. A significant minority of patients with inflammatory arthritis do not respond to these anti-TNF agents, they are associated with substantial risk of toxicity, require parenteral administration, and are extremely expensive. New antibody treatments in development can be divided into anti-cytokine agents, cell-targeted therapies, co-stimulation inhibitors, and treatments aimed at preventing joint erosion consequent on inflammation. This review discusses the state of the art in the development of these agents for management of this common group of diseases.

Liposomal daunorubicin and dexamethasone as a treatment for multiple myeloma - The DD protocol

Context and Objective: Lipasomial daunorubicin has been used to treat hematological malignancies, including multiple myelomo (MM). The goal was to evaluate efficacy, side-effects and toxicity of liposomal daunorubicin and dexamethasone (DD Protocol). Design and Setting: Prospective study of Sírio-Libonês, São Camilo, Brasil and Alemão Oswaldo Cruz hospitals. Methods: Twenty consecutive patients with active MM received four cycles of liposomal daunorubicin intravenously for two hours (25-30 mg/m 2/day) on three consecutive days per month, with oral dexamethasone, (10 mg every six hours) on four consecutive days three times a month. Results: The male/female ratio was 1:1 and median age 60. Nine patients were stage IIA, ten IIIA and one IIIB. The median from diagnosis to starting DD was 13 months. All patients received four cycles, except one. Fifteen had already received chemotherapy before DD. Responses of > 50% reduction in serum monoclonal paraprotein were observed in six patients after first cycle (30%), six after second (30%) and four after third (20%), while four (20%) did not obtain this. Initially, 17 patients (85%) had anemia: 12 (70%) achieved correction. Progressive disease was observed in three patients (15%), while one had minimal response, four (20%) partial and 12 (60%) complete. Hemotologlical toxicity was acceptable: three patients (15%) had neutrophils < 1,000/mm 3; none had thrombocyfopenia. Gastrointestinal toxicity was mild: nausea (10%), anorexio (15%) and no vomiting. Conclusions: This treatment has mild toxicity and good response rate. It may therefore be feasible before autologous bone marraw transplantation.

American visceral leishmaniasis: Factors associated with lethality in the state of São Paulo, Brazil

Objectives. To identify factors associated with death in visceral leishmaniasis (VL) cases. Patients and Methodology. We evaluated prognostic factors for death from VL in São Paulo state, Brazil, from 1999 to 2005. A prognostic study nested in a clinical cohort was carried out by data analysis of 376 medical files. A comparison between VL fatal cases and survivors was performed for clinical, laboratory, and biological features. Association between variables and death was assessed by univariate analysis, and the multiple logistic regression model was used to determine adjusted odds ratio for death, controlling confounding factors. Results. Data analysis identified 53 fatal cases out of 376 patients, between 1999 and 2005 in São Paulo state. Lethality was 14.1 (53/376), being higher in patients older than fifty years. The main causes of death were sepsis, bleeding, liver failure, and cardiotoxicity due to treatment. Variables significantly associated with death were severe anemia, bleeding, heart failure, jaundice, diarrhea, fever for more than sixty days, age older than fifty years, and antibiotic use. Conclusion. Educational health measures are needed for the general population and continuing education programs for health professionals working in the affected areas with the purpose of identifying and treating early cases, thus preventing the disease evolution towards death. © 2012 Geraldine Madalosso et al.

Intensified peginterferon α-2a dosing increases sustained virologic response rates in heavy, high viral load hepatitis c genotype 1 patients with high low-density lipoprotein

BACKGROUND AND GOAL: Patients infected with hepatitis C virus (HCV) with elevated low-density lipoprotein (LDL) levels achieve higher sustained virologic response (SVR) rates after peginterferon (PegIFN)/ribavirin treatment versus patients with lower LDL. Our aim was to determine whether SVR rates in patients with low/elevated LDL can be improved by dose intensification. STUDY: In PROGRESS, genotype 1 patients with baseline HCV RNA≥400,000 IU/mL and body weight ≥85 kg were randomized to 48 weeks of 180 μg/wk PegIFN α-2a (40 kDa) plus ribavirin (A: 1200 mg/d; B: 1400/1600 mg/d) or 12 weeks of 360 μg/wk PegIFN α-2a followed by 36 weeks of 180 μg/wk, plus ribavirin (C: 1200 mg/d; D: 1400/1600 mg/d). This retrospective analysis assessed SVR rates among patients with low (<100 mg/dL) or elevated (≥100 mg/dL) LDL. Patients with high LDL (n=256) had higher baseline HCV RNA (5.86×10 IU/mL) versus patients with low LDL (n=262; 4.02×10 IU/mL; P=0.0003). RESULTS: Multiple logistic regression analysis identified a significant interaction between PegIFN α-2a dose and LDL levels on SVR (P=0.0193). The only treatment-related SVR predictor in the nested multiple logistic regression was PegIFN α-2a dose among patients with elevated LDL (P=0.0074); therefore, data from the standard (A+B) and induction (C+D) dose arms were pooled. Among patients with low LDL, SVR rates were 40% and 35% in the standard and induction-dose groups, respectively; SVR rates in patients with high LDL were 44% and 60% (P=0.014), respectively. CONCLUSIONS: Intensified dosing of PegIFN α-2a increases SVR rates in patients with elevated LDL even with the difficult-to-cure characteristics of genotype 1, high baseline viral load, and high body weight. Copyright © 2013 by Lippincott Williams & Wilkins.

A comparison of drug use in driver fatalities and similarly exposed drivers. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Paediatric drug development of ramipril:reformulation, in vitro and in vivo evaluation

Ramipril is used mainly for the treatment of hypertension and to reduce incidence of fatality following heart attacks in patients who develop indications of congestive heart failure. In the paediatric population it is used most commonly for the treatment of heart failure, hypertension in type 1 diabetes and diabetic nephropathy. Due to the lack of a suitable liquid formulation, the current study evaluates the development of a range of oral liquid formulations of ramipril along with their in vitro and in vivo absorption studies. Three different formulation development approaches were studied: solubilisation using acetic acid as a co-solvent, complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) and suspension development using xanthan gum. Systematic optimisation of formulation parameters for the different strategies resulted in the development of products stable for twelve months at long term stability conditions. In vivo evaluation showed CMAX of 10.48 µg/mL for co-solvent, 13.04µg/ml for the suspension and 29.58µg/mL for the cyclodextrin based ramipril solution. Interestingly, both ramipril solution (co-solvent) and the suspension showed a TMAX of 2.5h, however, cyclodextrin based ramipril produced TMAX at 0.75h following administration. The results presented in this study provide translatable products for oral liquid ramipril which offer preferential paediatric use over existing alternatives.

Screening for drugs in oral fluid : illicit drug use and drug driving in a sample of urban and regional Queensland motorists

Police services in a number of Australian states and overseas jurisdictions have begun to implement or consider random road-side drug testing of drivers. This paper outlines research conducted to provide an estimate of the extent of drug driving in a sample of Queensland drivers in regional, rural and metropolitan areas. Oral fluid samples were collected from 2657 Queensland motorists and screened for illicit substances including cannabis (delta 9 tetrahydrocannibinol [THC]), amphetamines, ecstasy, and cocaine. Overall, 3.8% of the sample (n = 101) screened positive for at least one illicit substance, although multiple drugs were identified in a sample of 23 respondents. The most common drugs detected in oral fluid were ecstasy (n = 53), and cannabis (n = 46) followed by amphetamines (n = 23). A key finding was that cannabis was confirmed as the most common self-reported drug combined with driving and that individuals who tested positive to any drug through oral fluid analysis were also more likely to report the highest frequency of drug driving. Furthermore, a comparison between drug vs. drink driving detection rates for one region of the study, revealed a higher detection rate for drug driving (3.8%) vs. drink driving (0.8%). This research provides evidence that drug driving is relatively prevalent on Queensland roads, and may in fact be more common than drink driving. This paper will further outline the study findings’ and present possible directions for future drug driving research.

Rural and remote road safety study : final report

• Introduction: Concern and action for rural road safety is relatively new in Australia in comparison to the field of traffic safety as a whole. In 2003, a program of research was begun by the Centre for Accident Research and Road Safety - Queensland (CARRS-Q) and the Rural Health Research Unit (RHRU) at James Cook University to investigate factors contributing to serious rural road crashes in the North Queensland region. This project was funded by the Premier’s Department, Main Roads Department, Queensland Transport, QFleet, Queensland Rail, Queensland Ambulance Service, Department of Natural Resources and Queensland Police Service. Additional funding was provided by NRMA Insurance for a PhD scholarship. In-kind support was provided through the four hospitals used for data collection, namely Cairns Base Hospital, The Townsville Hospital, Mount Isa Hospital and Atherton Hospital.----- The primary aim of the project was to: Identify human factors related to the occurrence of serious traffic incidents in rural and remote areas of Australia, and to the trauma suffered by persons as a result of these incidents, using a sample drawn from a rural and remote area in North Queensland.----- The data and analyses presented in this report are the core findings from two broad studies: a general examination of fatalities and casualties from rural and remote crashes for the period 1 March 2004 until 30 June 2007, and a further linked case-comparison study of hospitalised patients compared with a sample of non-crash-involved drivers.----- • Method: The study was undertaken in rural North Queensland, as defined by the Australian Bureau of Statistics (ABS) statistical divisions of North Queensland, Far North Queensland and North-West Queensland. Urban areas surrounding Townsville, Thuringowa and Cairns were not included. The study methodology was centred on serious crashes, as defined by a resulting hospitalisation for 24 hours or more and/or a fatality. Crashes meeting this criteria within the North Queensland region between 1 March 2004 and 30 June 2007 were identified through hospital records and interviewed where possible. Additional data was sourced from coroner’s reports, the Queensland Transport road crash database, the Queensland Ambulance Service and the study hospitals in the region.----- This report is divided into chapters corresponding to analyses conducted on the collected crash and casualty data.----- Chapter 3 presents an overview of all crashes and casualties identified during the study period. Details are presented in regard to the demographics and road user types of casualties; the locations, times, types, and circumstances of crashes; along with the contributing circumstances of crashes.----- Chapter 4 presents the results of summary statistics for all casualties for which an interview was able to be conducted. Statistics are presented separately for drivers and riders, passengers, pedestrians and cyclists. Details are also presented separately for drivers and riders crashing in off-road and on-road settings. Results from questionnaire data are presented in relation to demographics; the experience of the crash in narrative form; vehicle characteristics and maintenance; trip characteristics (e.g. purpose and length of journey; periods of fatigue and monotony; distractions from driving task); driving history; alcohol and drug use; medical history; driving attitudes, intentions and behaviour; attitudes to enforcement; and experience of road safety advertising.----- Chapter 5 compares the above-listed questionnaire results between on-road crash-involved casualties and interviews conducted in the region with non-crash-involved persons. Direct comparisons as well as age and sex adjusted comparisons are presented.----- Chapter 6 presents information on those casualties who were admitted to one of the study hospitals during the study period. Brief information is given regarding the demographic characteristics of these casualties. Emergency services’ data is used to highlight the characteristics of patient retrieval and transport to and between hospitals. The major injuries resulting from the crashes are presented for each region of the body and analysed by vehicle type, occupant type, seatbelt status, helmet status, alcohol involvement and nature of crash. Estimates are provided of the costs associated with in-hospital treatment and retrieval.----- Chapter 7 describes the characteristics of the fatal casualties and the nature and circumstances of the crashes. Demographics, road user types, licence status, crash type and contributing factors for crashes are presented. Coronial data is provided in regard to contributing circumstances (including alcohol, drugs and medical conditions), cause of death, resulting injuries, and restraint and helmet use.----- Chapter 8 presents the results of a comparison between casualties’ crash descriptions and police-attributed crash circumstances. The relative frequency of contributing circumstances are compared both broadly within the categories of behavioural, environmental, vehicle related, medical and other groupings and specifically for circumstances within these groups.----- Chapter 9 reports on the associated research projects which have been undertaken on specific topics related to rural road safety.----- Finally, Chapter 10 reports on the conclusions and recommendations made from the program of research.---- • Major Recommendations : From the findings of these analyses, a number of major recommendations were made: + Male drivers and riders - Male drivers and riders should continue to be the focus of interventions, given their very high representation among rural and remote road crash fatalities and serious injuries.----- - The group of males aged between 30 and 50 years comprised the largest number of casualties and must also be targeted for change if there is to be a meaningful improvement in rural and remote road safety.----- + Motorcyclists - Single vehicle motorcycle crashes constitute over 80% of serious, on-road rural motorcycle crashes and need particular attention in development of policy and infrastructure.----- - The motorcycle safety consultation process currently being undertaken by Queensland Transport (via the "Motorbike Safety in Queensland - Consultation Paper") is strongly endorsed. As part of this process, particular attention needs to be given to initiatives designed to reduce rural and single vehicle motorcycle crashes.----- - The safety of off-road riders is a serious problem that falls outside the direct responsibility of either Transport or Health departments. Responsibility for this issue needs to be attributed to develop appropriate policy, regulations and countermeasures.----- + Road safety for Indigenous people - Continued resourcing and expansion of The Queensland Aboriginal Peoples and Torres Strait Islander Peoples Driver Licensing Program to meet the needs of remote and Indigenous communities with significantly lower licence ownership levels.----- - Increased attention needs to focus on the contribution of geographic disadvantage (remoteness) factors to remote and Indigenous road trauma.----- + Road environment - Speed is the ‘final common pathway’ in determining the severity of rural and remote crashes and rural speed limits should be reduced to 90km/hr for sealed off-highway roads and 80km/hr for all unsealed roads as recommended in the Austroads review and in line with the current Tasmanian government trial.----- - The Department of Main Roads should monitor rural crash clusters and where appropriate work with local authorities to conduct relevant audits and take mitigating action. - The international experts at the workshop reviewed the data and identified the need to focus particular attention on road design management for dangerous curves. They also indicated the need to maximise the use of audio-tactile linemarking (audible lines) and rumble strips to alert drivers to dangerous conditions and behaviours.----- + Trauma costs - In accordance with Queensland Health priorities, recognition should be given to the substantial financial costs associated with acute management of trauma resulting from serious rural and remote crashes.----- - Efforts should be made to develop a comprehensive, regionally specific costing formula for road trauma that incorporates the pre-hospital, hospital and post-hospital phases of care. This would inform health resource allocation and facilitate the evaluation of interventions.----- - The commitment of funds to the development of preventive strategies to reduce rural and remote crashes should take into account the potential cost savings associated with trauma.----- - A dedicated study of the rehabilitation needs and associated personal and healthcare costs arising from rural and remote road crashes should be undertaken.----- + Emergency services - While the study has demonstrated considerable efficiency in the response and retrieval systems of rural and remote North Queensland, relevant Intelligent Transport Systems technologies (such as vehicle alarm systems) to improve crash notification should be both developed and evaluated.----- + Enforcement - Alcohol and speed enforcement programs should target the period between 2 and 6pm because of the high numbers of crashes in the afternoon period throughout the rural region.----- + Drink driving - Courtesy buses should be advocated and schemes such as the Skipper project promoted as local drink driving countermeasures in line with the very high levels of community support for these measures identified in the hospital study.------ - Programs should be developed to target the high levels of alcohol consumption identified in rural and remote areas and related involvement in crashes.----- - Referrals to drink driving rehabilitation programs should be mandated for recidivist offenders.----- + Data requirements - Rural and remote road crashes should receive the same quality of attention as urban crashes. As such, it is strongly recommended that increased resources be committed to enable dedicated Forensic Crash Units to investigate rural and remote fatal and serious injury crashes.----- - Transport department records of rural and remote crashes should record the crash location using the national ARIA area classifications used by health departments as a means to better identifying rural crashes.----- - Rural and remote crashes tend to be unnoticed except in relatively infrequent rural reviews. They should receive the same level of attention and this could be achieved if fatalities and fatal crashes were coded by the ARIA classification system and included in regular crash reporting.----- - Health, Transport and Police agencies should collect a common, minimal set of data relating to road crashes and injuries, including presentations to small rural and remote health facilities.----- + Media and community education programmes - Interventions seeking to highlight the human contribution to crashes should be prioritised. Driver distraction, alcohol and inappropriate speed for the road conditions are key examples of such behaviours.----- - Promotion of basic safety behaviours such as the use of seatbelts and helmets should be given a renewed focus.----- - Knowledge, attitude and behavioural factors that have been identified for the hospital Brief Intervention Trial should be considered in developing safety campaigns for rural and remote people. For example challenging the myth of the dangerous ‘other’ or ‘non-local’ driver.----- - Special educational initiatives on the issues involved in rural and remote driving should be undertaken. For example the material used by Main Roads, the Australian Defence Force and local initiatives.

SNP technologies for drug discovery : a current review

Single nucleotide polymorphisms (SNPs) are unique genetic differences between individuals that contribute in significant ways to the determination of human variation including physical characteristics like height and appearance as well as less obvious traits such as personality, behaviour and disease susceptibility. SNPs can also significantly influence responses to pharmacotherapy and whether drugs will produce adverse reactions. The development of new drugs can be made far cheaper and more rapid by selecting participants in drug trials based on their genetically determined response to drugs. Technology that can rapidly and inexpensively genotype thousands of samples for thousands of SNPs at a time is therefore in high demand. With the completion of the human genome project, about 12 million true SNPs have been identified to date. However, most have not yet been associated with disease susceptibility or drug response. Testing for the appropriate drug response SNPs in a patient requiring treatment would enable individualised therapy with the right drug and dose administered correctly the first time. Many pharmaceutical companies are also interested in identifying SNPs associated with polygenic traits so novel therapeutic targets can be discovered. This review focuses on technologies that can be used for genotyping known SNPs as well as for the discovery of novel SNPs associated with drug response.

Adolescent protective behaviour to reduce drug and alcohol use, alcohol-related harm and interpersonal violence

Typically adolescents' friends are considered a risk factor for adolescent engagement in risk-taking. This study took a more novel approach, by examining adolescent friendship as a protective factor. In particular it investigated friends' potential to intervene to reduce risk-taking. 540 adolescents (mean age 13.47 years) were asked about their intention to intervene to reduce friends' alcohol, drug and alcohol-related harms and about psychosocial factors potentially associated with intervening. More than half indicated that they would intervene in friends' alcohol, drug use, alcohol-related harms and interpersonal violence. Intervening was associated with being female, having friends engage in overall less risk-taking and having greater school connectedness. The findings provide an important understanding of increasing adolescent protective behavior as a potential strategy to reduce alcohol and drug related harms.