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.

Prospective observational study of dementia and delirium in the acute hospital setting

Background: Dementia and delirium appear to be common among older patients admitted to acute hospitals, although there are few Australian data regarding these important conditions. Aim: The aim of this study was to determine the prevalence and incidence of dementia and delirium among older patients admitted to acute hospitals in Queensland and to profile these patients. Method: Prospective observational cohort study (n = 493) of patients aged 70 years and older admitted to general medical, general surgical and orthopaedic wards of four acute hospitals in Queensland between 2008 and 2010. Trained research nurses completed comprehensive geriatric assessments and obtained detailed information about each patient’s physical, cognitive and psychosocial functioning using the interRAI Acute Care and other standardised instruments. Nurses also visited patients daily to identify incident delirium. Two physicians independently reviewed patients’ medical records and assessments to establish the diagnosis of dementia and/or delirium. Results: Overall, 29.4% of patients (n = 145) were considered to have cognitive impairment, including 102 (20.7% of the total) who were considered to have dementia. This rate increased to 47.4% in the oldest patients (aged 90 years). The overall prevalence of delirium at admission was 9.7% (23.5% in patients with dementia), and the rate of incident delirium was 7.6% (14.7% in patients with dementia). Conclusion: The prevalence of dementia and delirium among older patients admitted to acute hospitals is high and is likely to increase with population aging. It is suggested that hospital design, staffing and processes should be attuned better to meet these patients’ needs.

Cognitive remediation : the foundation of psychosocial treatment of schizophrenia

Despite advances in psychopharmacology, schizophrenia remains a severely disabling illness. It is now appreciated that cognitive impairment mediates the functional disability associated with the disorder. Cognitive remediation which is defined as “a behavioural training based intervention that aims to improve cognitive processes (attention, memory, executive functioning, social cognition or meta cognition) with the goal of durability and generalization” is a therapeutic approach that improves cognition and when combined with other rehabilitation strategies improves real world functioning (Wykes et al., 2011).

The inaccuracy of national character stereotypes

Consensual stereotypes of some groups are relatively accurate, whereas others are not. Previous work suggesting that national character stereotypes are inaccurate has been criticized on several grounds. In this article we (a) provide arguments for the validity of assessed national mean trait levels as criteria for evaluating stereotype accuracy and (b) report new data on national character in 26 cultures from descriptions (N= 3323) of the typical male or female adolescent, adult, or old person in each. The average ratings were internally consistent and converged with independent stereotypes of the typical culture member, but were weakly related to objective assessments of personality. We argue that this conclusion is consistent with the broader literature on the inaccuracy of national character stereotypes

Combination therapy with gefitinib and rofecoxib in patients with platinum-pretreated relapsed non-small-cell lung cancer

Purpose: In non-small-cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) play major roles in tumorigenesis. This phase I/II study evaluated combined therapy with the EGFR tyrosine kinase inhibitor (TKI) gefitinib and the COX-2 inhibitor rofecoxib in platinum-pretreated, relapsed, metastatic NSCLC (n = 45). Patients and Methods: Gefitinib 250 mg/d was combined with rofecoxib (dose escalated from 12.5 to 25 to 50 mg/d through three cohorts, each n = 6). Because the rofecoxib maximum-tolerated dose was not reached, the 50 mg/d cohort was expanded for efficacy evaluation (n = 33). Results: Among the 42 assessable patients, there was one complete response (CR) and two partial responses (PRs) and 12 patients with stable disease (SD); disease control rate was 35.7% (95% CI, 21.6% to 52.0%). Median time to tumor progression was 55 days (95% CI, 47 to 70 days), and median survival was 144 days (95% CI, 103 to 190 days). In a pilot study, matrix-assisted laser desorption/ionization (MALDI) proteomics analysis of baseline serum samples could distinguish patients with an objective response from those with SD or progressive disease (PD), and those with disease control (CR, PR, and SD) from those with PD. The regimen was generally well tolerated, with predictable toxicities including skin rash and diarrhea. Conclusion: Gefitinib combined with rofecoxib provided disease control equivalent to that expected with single-agent gefitinib and was generally well tolerated. Baseline serum proteomics may help identify those patients most likely to benefit from EGFR TKIs. © 2007 by American Society of Clinical Oncology.

A phase II study of the modulation of 5-fluorouracil and folinic acid with high-dose infusional hydroxyurea in metastatic colorectal carcinoma

Background: Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, may potentiate the activity of 5-fluorouracil (5-FU) and folinic acid (FA) by reducing the deoxyribonucleotide pool available for DNA synthesis and repair. However as HU may inhibit the formation of 5-fluoro-2-deoxyuridine-5- monophosphate (FdUMP), one of the principal active metabolites of 5-FU, the scheduling of HU may be critical. In vitro experiments suggest that administration of HU following 5-FU, maintaining the concentration in the region of I mM for six or more hours, significantly enhances the efficacy of 5-FU. Patients and methods: 5-FU/FA was given as follows: days 1 and 2 - FA 250 mg/m 2 (max. 350 mg) over two hours followed by 5-FU 400 mg/m 2 by intravenous bolus (ivb) over 15 minutes and subsequently 5-FU 400 mg/m 2 infusion (ivi) over 22 hours. HU was administered on day 3 immediately after the 5-FU with 3 g ivb over 15 minutes followed by 12 g ivi over 12 hours. Results: Thirty patients were entered into the study. Median survival was nine months (range 1-51 + months). There were eight partial responses (28%, 95% CI: 13%-47%). The median duration of response was 6.5 (range 4-9 months). Grade 3-4 toxicities included neutropenia (grade 3 in eight patients and grade 4 in five), anaemia (grade 3 in one patient) and diarrhoea (grade 3 in two patients). Neutropenia was associated with pyrexia in two patients. Phlebitis at the infusion site occurred in five patients. The treatment was complicated by pulmonary embolism in one patient and deep venous thrombosis in another. Conclusion: HU administered in this schedule is well tolerated. Based on these results and those of other phase II studies, a randomised phase III study of 5-FU, FA and HU versus 5-FU and FA using the standard de Gramont schedule is recommended.

Recovery of transverse strain in high–stress tendons following exercise

Background. This study evaluated the time course of recovery of transverse strain in the Achilles and patellar tendons following a bout of resistance exercise. Methods. Seventeen healthy adults underwent sonographic examination of the right patellar (n = 9) or Achilles (n = 8) tendons immediately prior to and following 90 repetitions of weight–bearing exercise. Quadriceps and gastrocnemius exercise were performed against an effective resistance of 175% and 250% body weight, respectively. Sagittal tendon thickness was determined 20 mm from the tendon enthesis and transverse strain was repeatedly monitored over a 24 hour recovery period. Results. Resistance exercise resulted in an immediate decrease in Achilles (t7 = 10.6, P<.01) and patellar (t8 = 8.9, P<.01) tendon thickness, resulting in an average transverse strain of 0.14 ± 0.04 and 0.18 ± 0.05. While the average strain was not significantly different between tendons, older age was associated with a reduced transverse strain response (r=0.63, P<.01). Recovery of transverse strain, in contrast, was prolonged compared with the duration of loading and exponential in nature. The mean primary recovery time was not significantly different between Achilles (6.5 ± 3.2 hours) and patellar (7.1 ± 3.2 hours) tendons and body weight accounted for 62% and 64% of the variation in recovery time, respectively. Discussion. Despite structural and biochemical differences between the Achilles and patellar tendons [1], the mechanisms underlying transverse creep–recovery in vivo appear similar and are highly time dependent. Primary recovery required about 7 hours in healthy tendons, with full recovery requiring up to 24 hours. These in vivo recovery times are similar to those reported for axial creep recovery of the vertebral disc in vitro [2], and may be used clinically to guide physical activity to rest ratios in healthy adults. Optimal ratios for high–stress tendons in clinical populations, however, remain unknown and require further attention in light of the knowledge gained in this study.

Development of a bi-material representative volume element using damaged homogenisation approach

Most civil engineering structures are formed using a number of materials that are bonded to each other with their surface-to-surface interaction playing key role on the overall response of the structure. Unfortunately these interactions are extremely variable; simplified and extremely detailed models trialed to date prove quite complex. Models that assume perfect interaction, on the other hand, predict unsafe behavior. In this paper a damage mechanics based interaction between two materials of different softening properties is developed using homogenisation approach. This paper describes the process of developing a bi-material representative volume element (RVE) using damaged homogenisation approach. The novelty in this paper is the development of non-local transient damage identification algorithm. Numerical examples prove the stability of the approach for a simplified RVE and encourage application to other shapes of RVEs.

Foot ulcer simulation training (FUST) : are podiatrists FUST with long-term clinical confidence?

Background Foot ulcers are a leading cause of diabetes-related hospitalisations. Clinical training has been shown to be beneficial in foot ulcer management. Recently, improved self-confidence in podiatrists was reported immediately after foot ulcer simulation training (FUST) pilot programs. This study aimed to investigate the longer-term impacts of the FUST program on podiatrists’ self-confidence over 12 months in a larger sample. Methods Participants were podiatrists attending a two-day FUST course comprising web-based interactive learning, low-fidelity part-tasks and high-fidelity full clinical scenarios. Primary outcome measures included participants’ self-confidence measured pre-, (immediately) post-, 6-month post- and 12-month post-course via a purpose designed 21-item survey using a five-point Likert scale (1=Very limited, 5=Highly confident). Participants’ perceptions of knowledge gained, satisfaction, relevance and fidelity were also investigated. ANOVA and post hoc tests were used to test any differences between groups. Results Thirty-four participants completed FUST. Survey response rates were 100% (pre), 82% (post), 74% (6-month post), and 47% (12-month post). Overall mean scores were 3.13 (pre), 4.49 (post), 4.35 (6-month post) and 4.30 (12-month post) (p < 0.05); post hoc tests indicated no differences between the immediately, 6-month and 12-month post group scores (p > 0.05). Satisfaction, knowledge, relevance and fidelity were all rated highly. Conclusion This study suggests that significant short-term improvements in self-confidence to manage foot ulcers via simulation training are retained over the longer term. It is likely that improved self-confidence leads to improved foot ulcer clinical practice and outcomes; although this requires further research.

Prevalence of childhood sexual abuse among 2508 college students in 6 provinces of China [中国6省市2508名大学生儿童期性虐待经历回顾性调查]

OBJECTIVE To assess the prevalence of childhood sexual abuse (CSA) in college students and to explore the association of CSA with youth mental health problem. METHODS A retrospective survey was conducted among 2508 students (females 1360, males 1148) in Nov. 2003 to Mar. 2004. The students were from 6 colleges/universities in Beijing, Hebei, Shanxi, Jiangsu, Shaanxi and Anhui provinces of China. RESULTS Of the 2508 students, 24.8% of females and 17.6% of males reported one or more types of nonphysical contact CSA (females 20.0% vs. males 14.6%) or/and physical contact CSA (females 14.1% vs. males 7.8%) before the age of 16 years. Risk of any CSA was not associated with the existence of siblings (one-child vs. two-or more child families), rural/non-rural residence during childhood, or parental education. Compared with their peers who had no CSA, the students with CSA showed significantly higher mean scores of psychological symptoms of somatization, obsessiveness, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation and psychoticism. CONCLUSION The problem of CSA was not uncommon and there was a significant correlation between CSA experience and students mental health problems. More attention should be paid on CSA prevention and provision of health services for the victims.

Is the two hour recommended maximum driving time appropriate for both healthy older and treated obstructive sleep apnoea drivers?

Objectives The UK Department for Transport recommends taking a break from driving every 2 h. This study investigated: (i) if a 2 h drive time on a monotonous road is appropriate for OSA patients treated with CPAP, compared with healthy age matched controls, (ii) the impact of a night’s sleep restriction (with CPAP) and (iii) what happens if these patients miss one nights’ CPAP treatment. Methods About 19 healthy men aged 52–74 y (m = 66.2 y) and 19 OSA participants aged 50–75 y (m = 64.4 y) drove an interactive car simulator under monotonous motorway conditions for 2 h on two afternoons, in a counterbalanced design; (1) following a normal night’s sleep (8 h). (2) following a restricted night’s sleep (5 h), with normal CPAP use (3) following a night without CPAP treatment. (n = 11) Lane drifting incidents, indicative of falling asleep, were recorded for up to 2 h depending on competence to continue driving. Results Normal sleep: Controls drove for an average of 95.9 min (s.d. 37 min) and treated OSA drivers for 89.6 min (s.d. 29 min) without incident. 63.2% of controls and 42.1% of OSA drivers successfully completed the drive without an incident. Sleep restriction: 47.4% of controls and 26.3% OSA drivers finished without incident. Overall: controls drove for an average of 89.5 min (s.d. 39 min) and treated OSA drivers 65 min (s.d. 42 min) without incident. The effect of condition was significant [F(1.36) = 9.237, P < 0.05, eta2 = 0.204]. Stopping CPAP: 18.2% of drivers successfully completed the drive. Overall, participants drove for an average of 50.1 min (s.d. 38 min) without incident. The effect of condition was significant [F(2) = 8.8, P < 0.05, eta2 = 0.468]. Conclusion 52.6% of all drivers were able to complete a 2 hour drive under monotonous conditions after a full night’s sleep. Sleep restriction significantly affected both control and OSA drivers. We find evidence that treated OSA drivers are more impaired by sleep restriction than healthy control, as they were less able to sustain safely the 2 h drive without incidents. OSA drivers should be aware that non-compliance with CPAP can significantly impair driving performance. It may be appropriate to recommend older drivers take a break from driving every 90 min especially when undertaking a monotonous drive, as was the case here.

Text messaging to support off-campus clinical nursing facilitators : a descriptive survey

Background Managing large student cohorts can be a challenge for university academics, coordinating these units. Bachelor of Nursing programmes have the added challenge of managing multiple groups of students and clinical facilitators whilst completing clinical placement. Clear, time efficient and effective communication between coordinating academics and clinical facilitators is needed to ensure consistency between student and teaching groups and prompt management of emerging issues. Methods This study used a descriptive survey to explore the use of text messaging via a mobile phone, sent from coordinating academics to off-campus clinical facilitators, as an approach to providing direction and support. Results The response rate was 47.8% (n = 22). Correlations were found between the approachability of the coordinating academic and clinical facilitator perception that, a) the coordinating academic understood issues on clinical placement (r = 0.785, p < 0.001), and b) being part of the teaching team (r = 0.768, p < 0.001). Analysis of responses to qualitative questions revealed three themes: connection, approachability and collaboration. Conclusions This study demonstrates that use of regular text messages improves communication between coordinating academics and clinical facilitators. Findings suggest improved connection, approachability and collaboration between the coordinating academic and clinical facilitation staff.

Secretome and degradome profiling shows that Kallikrein-related peptidases 4, 5, 6, and 7 induce TGFβ-1 signaling in ovarian cancer cells

Kallikrein-related peptidases, in particular KLK4, 5, 6 and 7 (4-7), often have elevated expression levels in ovarian cancer. In OV-MZ-6 ovarian cancer cells, combined expression of KLK4-7 reduces cell adhesion and increases cell invasion and resistance to paclitaxel. The present work investigates how KLK4-7 shape the secreted proteome ("secretome") and proteolytic profile ("degradome") of ovarian cancer cells. The secretome comparison consistently identified >900 proteins in three replicate analyses. Expression of KLK4-7 predominantly affected the abundance of proteins involved in cell-cell communication. Among others, this includes increased levels of transforming growth factor β-1 (TGFβ-1). KLK4-7 co-transfected OV-MZ-6 cells share prominent features of elevated TGFβ-1 signaling, including increased abundance of neural cell adhesion molecule L1 (L1CAM). Augmented levels of TGFβ-1 and L1CAM upon expression of KLK4-7 were corroborated in vivo by an ovarian cancer xenograft model. The degradomic analysis showed that KLK4-7 expression mostly affected cleavage sites C-terminal to arginine, corresponding to the preference of kallikreins 4, 5 and 6. Putative kallikrein substrates include chemokines, such as growth differentiation factor 15 (GDF 15) and macrophage migration inhibitory factor (MIF). Proteolytic maturation of TGFβ-1 was also elevated. KLK4-7 have a pronounced, yet non-degrading impact on the secreted proteome, with a strong association between these proteases and TGFβ-1 signaling in tumor biology. © 2013 Federation of European Biochemical Societies.

The adaptive metabolic response to exercise-induced weight loss influences both energy expenditure and energy intake

BACKGROUND/OBJECTIVEs A decline in resting energy expenditure (REE) beyond that predicted from changes in body composition has been noted following dietary-induced weight loss. However, it is unknown whether a compensatory downregulation in REE also accompanies exercise (EX)-induced weight loss, or whether this adaptive metabolic response influences energy intake (EI). SUBJECTS/METHODS Thirty overweight and obese women (body mass index (BMI)=30.6±3.6 kg/m2) completed 12 weeks of supervised aerobic EX. Body composition, metabolism, EI and metabolic-related hormones were measured at baseline, week 6 and post intervention. The metabolic adaptation (MA), that is, difference between predicted and measured REE was also calculated post intervention (MApost), with REE predicted using a regression equation generated in an independent sample of 66 overweight and obese women (BMI=31.0±3.9 kg/m2). RESULTS Although mean predicted and measured REE did not differ post intervention, 43% of participants experienced a greater-than-expected decline in REE (−102.9±77.5 kcal per day). MApost was associated with the change in leptin (r=0.47; P=0.04), and the change in resting fat (r=0.52; P=0.01) and carbohydrate oxidation (r=−0.44; P=0.02). Furthermore, MApost was also associated with the change in EI following EX (r=−0.44; P=0.01). CONCLUSIONS Marked variability existed in the adaptive metabolic response to EX. Importantly, those who experienced a downregulation in REE also experienced an upregulation in EI, indicating that the adaptive metabolic response to EX influences both physiological and behavioural components of energy balance.

Predictors of initiating and maintaining active commuting to work using transport and public health perspectives in Australia

Objective To identify predictors for initiating and maintaining active commuting (AC) to work following the 2003 Australia's Walk to Work Day (WTWD) campaign. Methods Pre- and post-campaign telephone surveys of a cohort of working age (18–65years) adults (n = 1100, 55% response rate). Two dependent campaign outcomes were assessed: initiating or maintaining AC (i.e., walk/cycle and public transport) on a single day (WTWD), and increasing or maintaining health-enhancing active commuting (HEAC) level (≥ 30min/day) in a usual week following WTWD campaign. Results A significant population-level increase in HEAC (3.9%) was observed (McNemar's χ2 = 6.53, p = 0.01) with 136 (19.0%) achieving HEAC at post campaign. High confidence in incorporating walking into commute, being active pre-campaign and younger age (< 46years) were positively associated with both outcomes. The utility of AC for avoiding parking hassles (AOR = 2.1, 95% CI: 1.2–3.6), for less expense (AOR = 1.8, 95% CI: 1.1–3.1), for increasing one's health (AOR = 2.5, 95% CI: 1.1–5.6) and for clean air (AOR = 2.2, 95% CI: 1.0–4.4) predicted HEAC outcome whereas avoiding the stress of driving (AOR = 2.6, 95% CI: 1.4–5.0) and the hassle of parking predicted the single-day AC. Conclusions Transportation interventions targeting parking and costs could be further enhanced by emphasizing health benefits of AC. AC was less likely to occur among inactive employees.