CD4+ tumor infiltrating lymphocytes are prognostic and independent of R-IPI in patients with DLBCL receiving R-CHOP chemo-immunotherapy

Despite the Revised International Prognostic Index's (R-IPI) undoubted utility in diffuse large B-cell lymphoma (DLBCL), significant clinical heterogeneity within R-IPI categories persists. Emerging evidence indicates that circulating host immunity is a robust and R-IPI independent prognosticator, most likely reflecting the immune status of the intratumoral microenvironment. We hypothesized that direct quantification of immunity within lymphomatous tissue would better permit stratification within R-IPI categories. We analyzed 122 newly diagnosed consecutive DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemo-immunotherapy. Median follow-up was 4 years. As expected, the R-IPI was a significant predictor of outcome with 5-year overall survival (OS) 87% for very good, 87% for good, and 51% for poor-risk R-IPI scores (P < 0.001). Consistent with previous reports, systemic immunity also predicted outcome (86% OS for high lymphocyte to monocyte ratio [LMR], versus 63% with low LMR, P = 0.01). Multivariate analysis confirmed LMR as independently prognostic. Flow cytometry on fresh diagnostic lymphoma tissue, identified CD4+ T-cell infiltration as the most significant predictor of outcome with ≥23% infiltration dividing the cohort into high and low risk groups with regard to event-free survival (EFS, P = 0.007) and OS (P = 0.003). EFS and OS were independent of the R-IPI and LMR. Importantly, within very good/good R-IPI patients, CD4+ T-cells still distinguished patients with different 5 year OS (high 96% versus low 63%, P = 0.02). These results illustrate the importance of circulating and local intratumoral immunity in DLBCL treated with R-CHOP.

How distributional preferences shape incentives on (experimental) markets for credence goods

Credence goods markets suffer from inefficiencies caused by superior information of sellers about the surplus-maximizing quality. While standard theory predicts that equal mark-up prices solve the credence goods problem if customers can verify the quality received, experimental evidence indicates the opposite. We identify a lack of robustness of institutional design with respect to heterogeneity in distributional preferences as a possible cause and design new experiments that allow for parsimonious identification of sellers’ distributional types. Our results indicate that less than a fourth of the subjects behave according to standard theory’s assumption, the rest behaving either in line with non-standard selfish or in accordance with non-trivial other-regarding preferences. We discuss consequences of our findings for institutional design and agent selection.

Contracting for infrastructure projects as credence goods

Large infrastructure projects are a major responsibility of urban and regional governments, who usually lack expertise to fully specify the demanded projects. Contractors, typically experts on such projects due to experience with similar projects elsewhere, advise of the needed design in their bids. Producing the right design is nevertheless costly. We model such infrastructure projects taking into account their credence goods feature and the costly design effort they require and examine the performance of commonly used contracting methods. We show that when building costs are homogeneous and public information, multi-stage competitive bidding involving shortlisting of two contractors and contingent compensation of both contractors on design efforts outperforms sequential search and the traditional Design-and-Build approach. If building costs are private information of the contractors and are revealed to them after design cost is sunk, sequential search may be superior to the other two methods.

First-cycle rash and survival in patients with advanced non-small-cell lung cancer receiving cetuximab in combination with first-line chemotherapy : a subgroup analysis of data from the FLEX phase 3 study

Background: The randomised phase 3 First-Line Erbitux in Lung Cancer (FLEX) study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival compared with chemotherapy alone in the first-line treatment of advanced non-small-cell lung cancer (NSCLC). The main cetuximab-related side-effect was acne-like rash. Here, we assessed the association of this acne-like rash with clinical benefit. Methods: We did a subgroup analysis of patients in the FLEX study, which enrolled patients with advanced NSCLC whose tumours expressed epidermal growth factor receptor. Our landmark analysis assessed if the development of acne-like rash in the first 21 days of treatment (first-cycle rash) was associated with clinical outcome, on the basis of patients in the intention-to-treat population alive on day 21. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. Findings: 518 patients in the chemotherapy plus cetuximab group-290 of whom had first-cycle rash-and 540 patients in the chemotherapy alone group were alive on day 21. Patients in the chemotherapy plus cetuximab group with first-cycle rash had significantly prolonged overall survival compared with patients in the same treatment group without first-cycle rash (median 15·0 months [95% CI 12·8-16·4] vs 8·8 months [7·6-11·1]; hazard ratio [HR] 0·631 [0·515-0·774]; p<0·0001). Corresponding significant associations were also noted for progression-free survival (median 5·4 months [5·2-5·7] vs 4·3 months [4·1-5·3]; HR 0·741 [0·607-0·905]; p=0·0031) and response (rate 44·8% [39·0-50·8] vs 32·0% [26·0-38·5]; odds ratio 1·703 [1·186-2·448]; p=0·0039). Overall survival for patients without first-cycle rash was similar to that of patients that received chemotherapy alone (median 8·8 months [7·6-11·1] vs 10·3 months [9·6-11·3]; HR 1·085 [0·910-1·293]; p=0·36). The significant overall survival benefit for patients with first-cycle rash versus without was seen in all histology subgroups: adenocarcinoma (median 16·9 months, [14·1-20·6] vs 9·3 months [7·7-13·2]; HR 0·614 [0·453-0·832]; p=0·0015), squamous-cell carcinoma (median 13·2 months [10·6-16·0] vs 8·1 months [6·7-12·6]; HR 0·659 [0·472-0·921]; p=0·014), and carcinomas of other histology (median 12·6 months [9·2-16·4] vs 6·9 months [5·2-11·0]; HR 0·616 [0·392-0·966]; p=0·033). Interpretation: First-cycle rash was associated with a better outcome in patients with advanced NSCLC who received cisplatin and vinorelbine plus cetuximab as a first-line treatment. First-cycle rash might be a surrogate clinical marker that could be used to tailor cetuximab treatment for advanced NSCLC to those patients who would be most likely to derive a significant benefit. Funding: Merck KGaA. © 2011 Elsevier Ltd.

Thymidylate synthase expression and outcome of patients receiving pemetrexed for advanced nonsquamous non-small-cell lung cancer in a prospective blinded assessment phase II clinical trial

INTRODUCTION In retrospective analyses of patients with nonsquamous non-small-cell lung cancer treated with pemetrexed, low thymidylate synthase (TS) expression is associated with better clinical outcomes. This phase II study explored this association prospectively at the protein and mRNA-expression level. METHODS Treatment-naive patients with nonsquamous non-small-cell lung cancer (stage IIIB/IV) had four cycles of first-line chemotherapy with pemetrexed/cisplatin. Nonprogressing patients continued on pemetrexed maintenance until progression or maximum tolerability. TS expression (nucleus/cytoplasm/total) was assessed in diagnostic tissue samples by immunohistochemistry (IHC; H-scores), and quantitative reverse-transcriptase polymerase chain reaction. Cox regression was used to assess the association between H-scores and progression-free/overall survival (PFS/OS) distribution estimated by the Kaplan-Meier method. Maximal χ analysis identified optimal cutpoints between low TS- and high TS-expression groups, yielding maximal associations with PFS/OS. RESULTS The study enrolled 70 patients; of these 43 (61.4%) started maintenance treatment. In 60 patients with valid H-scores, median (m) PFS was 5.5 (95% confidence interval [CI], 3.9-6.9) months, mOS was 9.6 (95% CI, 7.3-15.7) months. Higher nuclear TS expression was significantly associated with shorter PFS and OS (primary analysis IHC, PFS: p < 0.0001; hazard ratio per 1-unit increase: 1.015; 95%CI, 1.008-1.021). At the optimal cutpoint of nuclear H-score (70), mPFS in the low TS- versus high TS-expression groups was 7.1 (5.7-8.3) versus 2.6 (1.3-4.1) months (p = 0.0015; hazard ratio = 0.28; 95%CI, 0.16-0.52; n = 40/20). Trends were similar for cytoplasm H-scores, quantitative reverse-transcriptase polymerase chain reaction and other clinical endpoints (OS, response, and disease control). CONCLUSIONS The primary endpoint was met; low TS expression was associated with longer PFS. Further randomized studies are needed to explore nuclear TS IHC expression as a potential biomarker of clinical outcomes for pemetrexed treatment in larger patient cohorts. © 2013 by the International Association for the Study of Lung Cancer.

A stepped-wedge cluster randomised controlled trial for evaluating rates of falls among inpatients in aged care rehabilitation units receiving tailored multimedia education in addition to usual care : a trial protocol

Introduction Falls are the most frequent adverse event reported in hospitals. Approximately 30% of in-hospital falls lead to an injury and up to 2% result in a fracture. A large randomised trial found that a trained health professional providing individualised falls prevention education to older inpatients reduced falls in a cognitively intact subgroup. This study aims to investigate whether this efficacious intervention can reduce falls and be clinically useful and cost-effective when delivered in the real-life clinical environment. Methods A stepped-wedge cluster randomised trial will be used across eight subacute units (clusters) which will be randomised to one of four dates to start the intervention. Usual care on these units includes patient's screening, assessment and implementation of individualised falls prevention strategies, ongoing staff training and environmental strategies. Patients with better levels of cognition (Mini-Mental State Examination >23/30) will receive the individualised education from a trained health professional in addition to usual care while patient's feedback received during education sessions will be provided to unit staff. Unit staff will receive training to assist in intervention delivery and to enhance uptake of strategies by patients. Falls data will be collected by two methods: case note audit by research assistants and the hospital falls reporting system. Cluster-level data including patient's admissions, length of stay and diagnosis will be collected from hospital systems. Data will be analysed allowing for correlation of outcomes (clustering) within units. An economic analysis will be undertaken which includes an incremental cost-effectiveness analysis. Ethics and dissemination The study was approved by The University of Notre Dame Australia Human Research Ethics Committee and local hospital ethics committees. Results The results will be disseminated through local site networks, and future funding and delivery of falls prevention programmes within WA Health will be informed. Results will also be disseminated through peer-reviewed publications and medical conferences.

Can we text you? A qualitative exploration of young unemployed job-seekers’ attitudes to receiving resilience-building SMS messages

A significant minority of young job-seekers remain unemployed for many months, and are at risk of developing depression. Both empirical studies and theoretical models suggest that cognitive, behavioural and social isolation factors interact to increase this risk. Thus, interventions that reduce or prevent depression in young unemployed job-seekers by boosting their resilience are required. Mobile phones may be an effective medium to deliver resilience-boosting support to young unemployed people by using SMS messages to interrupt the feedback loop of depression and social isolation. Three focus groups were conducted to explore young unemployed job-seekers’ attitudes to receiving and requesting regular SMS messages that would help them to feel supported and motivated while job-seeking. Participants reacted favourably to this proposal, and thought that it would be useful to continue to receive and request SMS messages for a few months after commencing employment as well.

The economics of credence goods : an experiment on the role of liability, verifiability, reputation and competition

Credence goods markets are characterized by asymmetric information between sellers and consumers that may give rise to inefficiencies, such as under- and overtreatment or market breakdown. We study in a large experiment with 936 participants the determinants for efficiency in credence goods markets. While theory predicts that liability or verifiability yield efficiency, we find that liability has a crucial, but verifiability at best a minor, effect. Allowing sellers to build up reputation has little influence, as predicted. Seller competition drives down prices and yields maximal trade, but does not lead to higher efficiency as long as liability is violated. (JEL D12, D82)

Age, physical inactivity, obesity, health conditions, and health-related quality of life among patients receiving conservative management for musculoskeletal disorders

Background Musculoskeletal conditions and insufficient physical activity have substantial personal and economic costs among contemporary aging societies. This study examined the age distribution, comorbid health conditions, body mass index (BMI), self-reported physical activity levels, and health-related quality of life of patients accessing ambulatory hospital clinics for musculoskeletal disorders. The study also investigated whether comorbidity, BMI, and self-reported physical activity were associated with patients’ health-related quality of life after adjusting for age as a potential confounder. Methods A cross-sectional survey was undertaken in three ambulatory hospital clinics for musculoskeletal disorders. Participants (n=224) reported their reason for referral, age, comorbid health conditions, BMI, physical activity levels (Active Australia Survey), and health-related quality of life (EQ-5D). Descriptive statistics and linear modeling were used to examine the associations between age, comorbidity, BMI, intensity and duration of physical activity, and health-related quality of life. Results The majority of patients (n=115, 51.3%) reported two or more comorbidities. In addition to other musculoskeletal conditions, common comorbidities included depression (n=41, 18.3%), hypertension (n=40, 17.9%), and diabetes (n=39, 17.4%). Approximately one-half of participants (n=110, 49.1%) self-reported insufficient physical activity to meet minimum recommended guidelines and 150 (67.0%) were overweight (n=56, 23.2%), obese (n=64, 28.6%), severely obese (n=16, 7.1%), or very severely obese (n=14, 6.3%), with a higher proportion of older patients affected. A generalized linear model indicated that, after adjusting for age, self-reported physical activity was positively associated (z=4.22, P<0.001), and comorbidities were negatively associated (z=-2.67, P<0.01) with patients’ health-related quality of life. Conclusion Older patients were more frequently affected by undesirable clinical attributes of comorbidity, obesity, and physical inactivity. However, findings from this investigation are compelling for the care of patients of all ages. Potential integration of physical activity behavior change or other effective lifestyle interventions into models of care for patients with musculoskeletal disorders is worthy of further investigation.

Contracting for infrastructure projects as credence goods

Large infrastructure projects are a major responsibility of urban and regional governments, who usually lack expertise to fully specify the demanded projects. Contractors, typically experts on such projects due to experience with similar projects,advise of the needed design as well as the cost of construction in their bids. Producing the right design is costly. We model such infrastructure projects taking into account their credence goods feature and the costly design effort they require and examine the performance of commonly used contracting methods. We show that when building costs are homogeneous and public information, simultaneous bidding involving shortlisting of two contractors and contingent compensation of both contractors on design efforts outperforms sequential search. If building costs are private information of the contractors and are revealed to them after design cost is sunk,sequential search may be superior to simultaneous bidding.

Nutritional risk of cancer patients receiving chemotherapy in the ambulatory care setting : a prospective study

Background Cancer itself can alter the metabolic and physiologic of the body's nutritional needs. As a result, some patients experience some degree of weight loss before the start of the treatment. Aim The aim of the study was to determine at which chemotherapy treatment cycle patients with cancer begin to exhibit signs and symptoms of malnutrition. Methods A prospective descriptive correlational design was used to assess the nutritional risk of 111 patients with cancer receiving chemotherapy in the ambulatory setting. The data were collected by using a nutritional screening tool. Findings The prevalence of malnutrition risk was 45% in patients undergoing the first cycle of chemotherapy. Patients who received the first three cycles of chemotherapy were 2.62 times more likely to develop malnutrition than those who received seven or more cycles. The risk of developing malnutrition varies depending on the type of cancer, the types of chemotherapy regime, the number of chemotherapy cycles, body mass index and the stage of cancer. Conclusion The study found about half of the patients had developed signs and symptoms of nutritional risk at cycle one. Hence, nutritional support may be required even before the start of chemotherapy.

The effectiveness of education or behavioral interventions on adherence to phosphate control in adults receiving hemodialysis: A systematic review protocol

The objective of this review is to identify the effectiveness of education or behavioral interventions on adherence to phosphate control in adults with end stage kidney disease (ESKD) receiving hemodialysis (HD).

A survey of patients' experience of pain and other symptoms while receiving care from palliative care services

Context In Australia, patients at the end of life with complex symptoms and needs are often referred to palliative care services (PCSs), but little is known about the symptoms of patients receiving palliative care in different settings. Objective To explore patients’ levels of pain and other symptoms while receiving care from PCSs. Method PCSs registered through Australia's national Palliative Care Outcomes Collaboration (PCOC) were invited to participate in a survey between 2008 and 2011. Patients (or if unable, a proxy) were invited to complete the Palliative Care Outcome Scale. Results Questionnaires were completed for 1800 patients. One-quarter of participants reported severe pain, 20% reported severe ‘other symptoms’, 20% reported severe patient anxiety, 45% reported severe family anxiety, 66% experienced depressed feelings and 19% reported severe problems with self-worth. Participants receiving care in major cities reported higher levels of depressed feelings than participants in inner regional areas. Participants receiving care in community and combined service settings reported higher levels of need for information, more concerns about wasted time, and lower levels of family anxiety and depressed feelings when compared to inpatients. Participants in community settings had lower levels of concern about practical matters than inpatients. Conclusions Patients receiving care from Australian PCSs have physical and psychosocial concerns that are often complex and rated as ‘severe’. Our findings highlight the importance of routine, comprehensive assessment of patients’ concerns and the need for Specialist Palliative Care clinicians to be vigilant in addressing pain and other symptoms in a timely, systematic and holistic manner, whatever the care setting.

How does symptom burden differ in people with advanced CKD who are non-dialysis or currently receiving dialysis?

Background Chronic kidney disease (CKD) leads to a range of symptoms which are often under-recognised. Little is known about the full range of symptoms, particularly in who are pre-dialysis. Understanding symptom prevalence, distress, severity and frequency will help prioritise symptom management. Aims To examine symptom burden in advanced CKD (stages 4 and 5) and compare the symptom experience between those receiving dialysis or those who are pre-dialysis. Methods Using a cross-sectional design, a convenience sample of 436 people from three hospitals completed the Modified Dialysis Symptom Index (MDSI). Demographic and renal history data was also collected. Based on the 32 symptoms, we compared the prevalence, severity, distress and frequency of each symptom by treatment modality. Results Mean age was 48 years (range 18-87 years) and 53% were male. 75.5% (haemodialysis = 287; peritoneal dialysis = 42) were receiving dialysis and 24.5% (n = 107) were pre-dialysis. Overall, the mean symptom prevalence was 12.6 ± 7.9 and the most prevalent symptoms were fatigue (77%), bone or joint pain (60.3%) and itching (59.6%) across all CKD groups. The distress, severity and frequency of the symptoms were higher in the dialysis group. However, a higher frequency of psychological symptoms (worrying, feeling nervous and depression) were reported in the pre-dialysis group. Implication for clinical practice Patients with advanced CKD have a high symptom burden with those who are pre-dialysis needing greater psychological support. The MDSI could be used in nursing practice to screen patients for symptoms which could lead to timely and appropriate interventions.