Cryotherapy for docetaxel-induced hand and nail toxicity: Randomised control trial

Purpose This study investigated the efficacy and safety of cryotherapy, in the form of frozen gel gloves, in relation to docetaxel-induced hand and fingernail toxicities. Patients and methods After piloting with 21 patients, a consecutive series sample of patients (n=53) prescribed docetaxel every three weeks, for a minimum of three cycles, was enrolled in this randomised control trial. Participants acted as their own control, with the frozen gel glove worn on one randomised hand for 15 minutes prior to infusion, for the duration of the infusion, and for 15 minutes of after completion of treatment. Hand and nail toxicities were evaluated by two blinded assessors according to CTCAE.v4 criteria. To assess the potential for cross-infection of multi-use gloves, microbial culture and sensitivity swabs were taken of each glove at every tenth use. Results Of the 53 participants enrolled in the main study, 21 provided evaluable data. There was a 60% withdrawal rate due to patient discomfort with the intervention. The mean incidence and severity of toxicities in all evaluable cycles in control and intervention hands respectively were erythroderma Grade 1 (5%/5%); nail discolouration Grade 1 (81%/67%); nail loss Grade 1 (19%/19%) and nail ridging Grade 1 (57%/57%). No significant differences were determined between hand conditions in terms of time to event, nor in terms of toxicity in gloved and non-gloved hands. Conclusion While cryotherapy in the form of frozen gloves for the cutaneous toxicities associated with docetaxel is safe, its limited efficacy, patient discomfort and some logistical issues preclude its use in our clinical setting.

MMP-9 and the epidermal growth factor signal pathway in non-small cell lung cancer

Background Matrix metalloproteinase (MMP)-9 is an endopeptidase that digests basement membrane type-IV collagen. Enhanced expression has been related to tumour progression in a number of systems. The control of MMP expression is complex, but recently epidermal growth actor receptor (EGFR) activity has been implicated in up-regulation of MMP-9 in tumour cells in vitro. Aims To evaluate interrelations between MMP-9 and EGFR expression in non-small cell lung cancer (NSCLC) and to assess the impact of expression on survival. Methods This is a retrospective study of 152 patients who underwent resection for stage I-IIIa NSCLC with a post-operative survival >60 days. Minimum follow-up was 2 years. Standard ABC immunohistochemistry was performed on 4μm paraffin-embedded sections from the tumour periphery using monoclonal antibodies to MMP-9 and EGFR. Results: MMP-9 was expressed in the tumour cells of 79/152 (52%) cases. EGFR expression was found in 86/152 (57%) cases [membranous 51/152 (34%), cytoplasmic 35/152 (23%)]. MMP-9 expression was associated with poor outcome (p=0.04). Membranous, cytoplasmic and overall EGFR expression were not associated with outcome (p=0.29, p=0.85 and p=0.41 respectively). There was a strong correlation between MMP-9 expression and EGFR expression (p=0.001) and EGFR membranous expression (p=0.01) but not with cytoplasmic EGFR expression (p=0.28). Co-expression of MMP-9 and EGFR (36%) conferred a worse prognosis (p=0.003). Subset analysis revealed only MMP-9 and membranous EGFR co-expression (22%) was associated with poor outcome (p=0.008). Conclusions Our results show that MMP-9 and EGFR are co-expressed in NSCLC. This finding suggests the EGFR signalling pathway may play an important role in the invasive behaviour of NSCLC via specific upregulation of MMP-9. The co-expression of these markers also confers a poor prognosis.

Expression and prognostic influence of MMP-2, MMP-9 and TIMP-2 in non-small cell lung cancer

Background Matrix metalloproteinases (MMPs) are a family of endopeptidases that digest the extracellular matrix (ECM). Overexpression of different MMPs has been shown to promote tumour cell invasion in vitro. Tissue inhibitors of matrix metalloproteinases (TIMPs) are specific inhibitors of MMPs that also possess growth-promoting properties. Aims To analyse the expression profile of MMP-2, MMP-9 and TIMP-2 in non-small cell lung cancer (NSCLC) and to assess the impact of expression on survival. Methods This is a retrospective study of patients who underwent resection for stage I-IIIa NSCLC with a post-operative survival >60 days. Patient follow up was a minimum of 2 years. Standard ABC immunohistochemistry was performed on 4μm paraffin-embedded sections from the tumour periphery using monoclonal antibodies to MMP-2, MMP-9 and TIMP-2. Results The results of the immunohistochemistry are set out below. marker tumour expression log-rank survival stromal expression log-rank survival MMP-2 9/72 (13%) p=0.10 34/72 (47%) p=0.34 MMP-9 79/152 (52%) p=0.04* 69/152 (45%) p=0.84 TIMP-2 28/90 (31%) p=0.04* 66/90 (73%) p=0.90 Two or more 16/59 (27%) p=0.007* There were no associations between expression and clinicopathological findings for any tumour marker. There was co-expression of MMP-2 and MMP-9 in tumour cells (p=0.01). Conclusions MMP-2, MMP-9 and TIMP-2 are expressed in NSCLC. MMP-9 and TIMP-2 tumour expression correlate with a poor outcome (both p=0.04) and are potential prognostic markers for NSCLC. Cumulative expression of two or more MMPs/TIMPs may also have increased prognostic significance. Proteases and their inhibitors are novel targets for therapeutic intervention and should be evaluated in NSCLC.

Prognostic significance of platelet and microvessel counts in operable non-small cell lung cancer

Background: Microvessel density, an indirect measure of angiogenesis, has been shown to be an independent prognostic marker in many solid tumours including non-small cell lung cancer (NSCLC). Platelets transport and release angiogenic growth factors. Platelets are increasingly likely to adhere to tumour microvessels due to raised expression of platelet-binding proteins and stasis in blood-flow. Increased vascular permeability in tumour microvessels facilitates platelet extravasation into the extracellular matrix. Adherence and extravasation both lead to platelet activation and release of growth factors capable of instigating the angiogenic process. Methods: A total of 181 patients were identified who underwent resection of stage I-IIIa NSCLC with a post-operative survival >60 days. Patients were followed-up for a minimum of 24 months. Sections from the tumour periphery were stained for the endothelial marker CD34 (Novocastra NCL-END) using standard ABC immunohistochemistry. Chalkley counting was used to assess microvessel density. Results: A pre-operative platelet count greater than the median and above the normal range (>400) was associated with a poor outcome (P = 0.01 and P = 0.04, respectively). Tumours with an above median and high Chalkley count (upper tertile) had a worse prognosis (P = 0.007 and P = 0.0006, respectively). There was no association between platelet count and Chalkley count. Conclusions: Platelet and microvessel counts are both potential prognostic markers for NSCLC. The role of platelets in the angiogenic process needs to be further investigated. (C) 2000 Elsevier Science Ireland Ltd.

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.

What makes juvenile offenders different from adult offenders?

Historically, children in criminal justice proceedings were treated much the same as adults and subject to the same criminal justice processes as adults. Until the early twentieth century, children in Australia were even subjected to the same penalties as adults, including hard labour and corporal and capital punishment (Carrington & Pereira 2009). Until the mid-nineteenth century, there was no separate category of ’juvenile offender’ in Western legal systems and children as young as six years of age were incarcerated in Australian prisons (Cunneen & White 2007). It is widely acknowledged today, however, both in Australia and internationally, that juveniles should be subject to a system of criminal justice that is separate from the adult system and that recognises their inexperience and immaturity. As such, juveniles are typically dealt with separately from adults and treated less harshly than their adult counterparts. The United Nations’ (1985: 2) Standard Minimum Rules for the Administration of Juvenile Justice (the ‘Beijing Rules’) stress the importance of nations establishing a set of laws, rules and provisions specifically applicable to juvenile offenders and institutions and bodies entrusted with the functions of the administration of juvenile justice and designed to meet the varying needs of juvenile offenders, while protecting their basic rights. In each Australian jurisdiction, except Queensland, a juvenile is defined as a person aged between 10 and 17 years of age, inclusive. In Queensland, a juvenile is defined as a person aged between 10 and 16 years, inclusive. In all jurisdictions, the minimum age of criminal responsibility is 10 years. That is, children under 10 years of age cannot be held legally responsible for their actions.

A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer

Purpose: This randomised trial was designed to investigate the activity and toxicity of continuous infusion etoposide phosphate (EP), targeting a plasma etoposide concentration of either 3 μg/ml for five days (5d) or 1 μg/ml for 15 days (15d), in previously untreated SCLC patients with extensive disease. Patients and methods: EP was used as a single agent. Plasma etoposide concentration was monitored on days 2 and 4 in patients receiving 5d EP and on days 2, 5, 8 and 11 in patients receiving 15d EP, with infusion modification to ensure target concentrations were achieved. Treatment was repeated every 21 days for up to six cycles, with a 25% reduction in target concentration in patients with toxicity. Results: The study has closed early after entry of 29 patients (14 with 5d EP, 15 with 15d EP). Objective responses were seen in seven of 12 (58%, confidence interval (CI): 27%-85%) evaluable patients after 5d EP, and two of 14 (14%, CI: 4%42%) evaluable patients after 15d EP (P = 0.038). Grade 3 or 4 neutropenia or leucopenia during the first cycle of treatment was observed in six of 12 patients after 5d EP and 0/14 patients after 15d EP (P = 0.004), with median nadir WBC count of 2.6 x 109/1 after 5d and 5.0 x 109/1 after 15d EP (P = 0.017). Only one of 49 cycles of 15d EP was associated with grade 3 or worse haematological toxicity, compared to 14 of 61 cycles of 5d EP. Conclusions: Although the number of patients entered into this trial was small, the low activity seen at 1 μg/ml in the 15d arm suggests that this concentration is below the therapeutic window in this setting. Further concentration- controlled studies with prolonged EP infusions are required.

Determinants of drink-driving and association between drink-driving and road traffic fatalities in Ghana

Background Drink-driving has been implicated in many road traffic crashes in the world. Consequently, the developed countries have prioritized drink-driving research. Contrary, drink-driving research has not attained any meaningful consideration in many developing countries. It is therefore imperative to intensify drink-driving research so as to provide research driven solutions to the menace. Aims The objective is to establish determinants of drink-driving and its association with traffic crashes in Ghana. Methods A randomized roadside breathalyzer survey was conducted. A multivariable logistic regression was used to establish significant determinants of drink-driving and a bivariate logistic regression to establish the association between drink–driving and road traffic crashes in Ghana. Results In total, 2,736 motorists were randomly stopped for breath testing of whom 8.7% tested positive for alcohol. Among the total participants, 5.5% exceeded the legal BAC limit of 0.08%. Formal education is associated with a reduced likelihood of drink-driving compared with drivers without formal education. The propensity to drink-drive is 1.8 times higher among illiterate drivers compared with drivers with basic education. Young adult drivers also recorded elevated likelihoods for driving under alcohol impairment compared with adult drivers. The odds of drink-driving among truck drivers is OR=1.81, (95% CI=1.16 to 2.82) and two wheeler riders is OR=1.41, (95% CI=0.47 to 4.28) compared with car drivers. Contrary to general perception, commercial car drivers have a significant reduced likelihood of 41%, OR=0.59, (95% CI=0.38 to 0.92) compared with the private car driver. Bivariate analysis conducted showed a significant association between the proportion of drivers exceeding the legal BAC limit and road traffic fatalities, p<0.001. The model predicts a 1% increase in the proportion of drivers exceeding the legal BAC to be associated with a 4% increase in road traffic fatalities, 95% CI= 3% to 5% and vice versa. Discussion and conclusion A positive and significant association between roadside alcohol prevalence and road traffic fatality has been established. Scaling up roadside breath test, determining standard drink and disseminating to the populace and formulating policies targeting the youth such as increasing minimum legal drinking age and reduced legal BAC limit for the youth and novice drivers might improve drink-driving related crashes in Ghana.

Phase III trial comparing paclitaxel poliglumex (CT-2103, PPX) in combination with carboplatin versus standard paclitaxel and carboplatin in the treatment of PS 2 patients with chemotherapy-naïve advanced non-small cell lung cancer

INTRODUCTION: Performance status (PS) 2 patients with non-small cell lung cancer (NSCLC) experience more toxicity, lower response rates, and shorter survival times than healthier patients treated with standard chemotherapy. Paclitaxel poliglumex (PPX), a macromolecule drug conjugate of paclitaxel and polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel and may lead to increased concentrations in tumors due to enhanced vascular permeability. METHODS: Chemotherapy-naive PS 2 patients with advanced NSCLC were randomized to receive carboplatin (area under the curve = 6) and either PPX (210 mg/m/10 min without routine steroid premedication) or paclitaxel (225 mg/m/3 h with standard premedication) every 3 weeks. The primary end point was overall survival. RESULTS: A total of 400 patients were enrolled. Alopecia, arthralgias/myalgias, and cardiac events were significantly less frequent with PPX/carboplatin, whereas grade ≥3 neutropenia and grade 3 neuropathy showed a trend of worsening. There was no significant difference in the incidence of hypersensitivity reactions despite the absence of routine premedication in the PPX arm. Overall survival was similar between treatment arms (hazard ratio, 0.97; log rank p = 0.769). Median and 1-year survival rates were 7.9 months and 31%, for PPX versus 8 months and 31% for paclitaxel. Disease control rates were 64% and 69% for PPX and paclitaxel, respectively. Time to progression was similar: 3.9 months for PPX/carboplatin versus 4.6 months for paclitaxel/carboplatin (p = 0.210). CONCLUSION: PPX/carboplatin failed to provide superior survival compared with paclitaxel/carboplatin in the first-line treatment of PS 2 patients with NSCLC, but the results with respect to progression-free survival and overall survival were comparable and the PPX regimen was more convenient. © 2008International Association for the Study of Lung Cancer.

SRL 172 (killed Mycobacterium vaccae) in addition to standard chemotherapy improves quality of life without affecting survival, in patients with advanced non-small-cell lung cancer : phase III results

Background: This open-label, randomised phase III study was designed to further investigate the clinical activity and safety of SRL172 (killed Mycobacterium vaccae suspension) with chemotherapy in the treatment of non-small-cell lung cancer (NSCLC). Patients and methods: Patients were randomised to receive platinum-based chemotherapy, consisting of up to six cycles of MVP (mitomycin, vinblastine and cisplatin or carboplatin) with (210 patients) or without (209 patients) monthly SRL172. Results: There was no statistical difference between the two groups in overall survival (primary efficacy end point) over the course of the study (median overall survival of 223 days versus 225 days; P = 0.65). However, a higher proportion of patients were alive at the end of the 15-week treatment phase in the chemotherapy plus SRL172 group (90%), than in the chemotherapy alone group (83%) (P = 0.061). At the end of the treatment phase, the response rate was 37% in the combined group and 33% in the chemotherapy alone group. Patients in the chemotherapy alone group had greater deterioration in their Global Health Status score (-14.3) than patients in the chemotherapy plus SRL172 group (-6.6) (P = 0.02). Conclusion: In this non-placebo controlled trial, SRL172 when added to standard cancer chemotherapy significantly improved patient quality of life without affecting overall survival times. © 2004 European Society for Medical Oncology.

Re-think, Re-generate, Re-envisage fashionable sun-safe apparel

Design is a way of thinking and working that systematically can create immense societal change. In particular, fashion design is one of the most progressively forward-looking creative and commercial generators that can envisage and initiate meaningful visual and social transformation. If we look back in time at the authority of fashion, many trends have significantly induced visual norms aligning glamour and health with tanned skin - numerous examples exist, including Vogue magazine proclaiming (front-cover) that ‘The 1929 girl must be tanned’. Indeed, in a contemporary landscape, fashion trends continue to re-generate apparel that, in-the-main, has limited design resolution connected to sun safety, and surprisingly many designers elect to ignore this vital and potentially lucrative market segment. In a context with soaring skin cancer rates, how can this powerful design medium of fashion make a positive difference to sun protection; what is the untapped potential for young design talent to connect with the health sector for skin cancer prevention; and, how can fashion designers be swayed to design and produce fashionable sun-safe apparel, that address pertinent issues including heat build up, comfort and transformability? Through a case study approach, examining emergent fashion designers, this paper will propose that astute and novel avenues exist for fashion to re-think sun protective apparel, including: generation of crucial design standards for sun-safe apparel, exploration of co-branding opportunities, advancement of fashion forecasting to connect modesty of body coverage to fashion trends and alignment of the market segment to re-envisage a critical mass for fashionable sun-safe apparel.

Lessons from the 4-hour standard in England for Australia

Australia is in the process of making the most important change to its health care system since the implementation of Medicare.1 We agree with Cameron and Cooke that there are important lessons for Australia from the implementation of the 4-hour rule in the United Kingdom. As in Robert Zemeckis’s 1985 movie classic, Back to the future, the old question of “If I had the opportunity to do something again, what would I have done differently?” applies. We challenge the assumption that Australia is embarking on something that the UK has recently abandoned. The UK has not actually abandoned the 4-hour rule but expanded it into a suite of eight indicators that include three time-based measures, including total time in the emergency department (ED).

Treatment rationale study design for the MetLung trial : a randomized, double-blind phase III study of onartuzumab (MetMAb) in combination with erlotinib versus erlotinib alone in patients who have received standard chemotherapy for stage IIIB or IV met-positive non-small-cell lung cancer

We present the treatment rationale and study design of the MetLung phase III study. This study will investigate onartuzumab (MetMAb) in combination with erlotinib compared with erlotinib alone, as second- or third-line treatment, in patients with advanced non-small-cell lung cancer (NSCLC) who are Met-positive by immunohistochemistry. Approximately 490 patients (245 per treatment arm) will receive erlotinib (150 mg oral daily) plus onartuzumab or placebo (15 mg/kg intravenous every 3 weeks) until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death. The efficacy objectives of this study are to compare overall survival (OS) (primary endpoint), progression-free survival, and response rates between the 2 treatment arms. In addition, safety, quality of life, pharmacokinetics, and translational research will be investigated across treatment arms. If the primary objective (OS) is achieved, this study will provide robust results toward an alternative treatment option for patients with Met-positive second- or third-line NSCLC. © 2012 Elsevier Inc. All Rights Reserved.