Fissure Seal or Fluoride Varnish? A Randomized Trial of Relative Effectiveness.

Fissure sealant (FS) and fluoride varnish (FV) are effective in preventing dental caries when compared with a no-treatment control. However, the relative clinical effectiveness of these interventions is uncertain. The objective of the study was to compare the clinical effectiveness of FS and FV in preventing dental caries in first permanent molars (FPMs) in 6- to 7-y-olds. The study design was a randomized clinical trial, with 2 parallel arms. The setting was a targeted-population program that used mobile dental clinics in schools located within areas of high social and economic deprivation in South Wales. A total of 1,016 children were randomized 1:1 to receive either FS or FV. Resin-based FS was applied to caries-free FPMs and maintained at 6-mo intervals. FV was applied at baseline and at 6-mo intervals for 3 y. The main outcome measures were the proportion of children developing caries into dentine (D4-6MFT) on any 1 of up to 4 treated FPMs after 36 mo. At 36 mo, 835 (82%) children remained: 417 in the FS arm and 418 in the FV arm. A smaller proportion of children who received FV ( n = 73, 17.5%) versus FS ( n = 82, 19.6%) developed caries into dentine on at least 1 FPM (odds ratio [OR] = 0.84; 95% CI, 0.59 to 1.21; P = 0.35), a nonstatistically significant difference between FS and FV treatments. The results were similar when the number of newly decayed teeth (OR = 0.86; 95% CI, 0.60 to 1.22) and tooth surfaces (OR = 0.85; 95% CI, 0.59 to 1.21) were examined. In a community oral health program, semiannual application of FV resulted in caries prevention that was not significantly different from that obtained by applying and maintaining FS after 36 mo (EudraCT: 2010-023476-23; ISRCTN: ISRCTN17029222).

A systematic review to establish health-related quality-of-life domains for intervention targets in cancer cachexia.

OBJECTIVES: To develop a model of the impact of cancer cachexia on patients by identifying the relevant health-related quality-of-life (HRQOL) issues, and to use the model to identify opportunities for intervention. METHODS: Standard systematic review methods were followed to identify papers which included direct quotes from cancer patients with cachexia or problems with eating or weight loss. Following thematic synthesis methodology, the quotes were coded, and themes and metathemes were extracted. The metathemes were used to develop a model of the patient's experience of cachexia. RESULTS: 18 relevant papers were identified which, in total, contained interviews with more than 250 patients. 226 patient quotes were extracted from the papers and 171 codes. 26 themes and 8 metathemes were formulated. The model developed from the metathemes demonstrated a direct link between eating and food problems and negative emotions and also a link mediated by the associated physical decline. These links provide opportunities for interventions. CONCLUSIONS: There are a vast number of HRQOL issues associated with cancer cachexia as identified from patients' own words. The model generated from these issues indicates that relationships, coping and knowledge of the condition are important components of new psychosocial interventions.

Quality-of-life outcomes following pelvic exenteration for primary rectal cancer.

BACKGROUND: For patients with locally advanced tumours and contiguous organ involvement, pelvic exenteration (PE) can offer cure with relatively low mortality. The literature surrounding quality of life (QoL) in patients undergoing PE is limited. Furthermore, there are no matched comparisons of QoL between abdominoperineal resection (APR) and PE. The aim of this study was to compare differences in long-term QoL for patients with primary rectal cancer undergoing APR versus PE. METHODS: All patients who underwent either APR or PE between January 2011 and December 2012 were identified. Patients were asked to complete the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire before surgery and 2 weeks afterwards. Subsequent questionnaires were requested at 3, 6, 12 and 24 months after operation. RESULTS: A total of 110 patients were included in the study (54 APR, 56 PE). Median length of stay following operation was 11 (range 3-70) days for APR and 15 (7-84) days for PE. Patients undergoing PE experienced lower physical (mean score 42 versus 56; P = 0.010), role (20 versus 33; P = 0.047), emotional (57 versus 73; P = 0.010) and social (34 versus 52; P = 0.005) functional levels 2 weeks after surgery. Long-term dyspnoea and financial worries were experienced only after PE. Patients undergoing PE had a lower overall global health status at 2 weeks after operation (40 versus 53; P = 0.012). Levels were comparable between groups from 3 months after surgery. CONCLUSION: QoL recovery following PE was equivalent to that after APR alone. Patients should not be denied exenterative surgery based on perceived poor QoL.

Effectiveness and cost-effectiveness of a universal parenting skills programme in deprived communities: multicentre randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness and cost utility of a universally provided early years parenting programme. DESIGN: Multicentre randomised controlled trial with cost-effectiveness analysis. SETTING: Early years centres in four deprived areas of South Wales. PARTICIPANTS: Families with children aged between 2 and 4 years. 286 families were recruited and randomly allocated to the intervention or waiting list control. INTERVENTION: The Family Links Nurturing Programme (FLNP), a 10-week course with weekly 2 h facilitated group sessions. MAIN OUTCOME MEASURES: Negative and supportive parenting, child and parental well-being and costs assessed before the intervention, following the course (3 months) and at 9 months using standardised measures. RESULTS: There were no significant differences in primary or secondary outcomes between trial arms at 3 or 9 months. With '+' indicating improvement, difference in change in negative parenting score at 9 months was +0.90 (95%CI -1.90 to 3.69); in supportive parenting, +0.17 (95%CI -0.61 to 0.94); and 12 of the 17 secondary outcomes showed a non-significant positive effect in the FLNP arm. Based on changes in parental well-being (SF-12), the cost per quality-adjusted life year (QALY) gained was estimated to be £34 913 (range 21 485-46 578) over 5 years and £18 954 (range 11 664-25 287) over 10 years. Probability of cost per QALY gained below £30 000 was 47% at 5 years and 57% at 10 years. Attendance was low: 34% of intervention families attended no sessions (n=48); only 47% completed the course (n=68). Also, 19% of control families attended a parenting programme before 9-month follow-up. CONCLUSIONS: Our trial has not found evidence of clinical or cost utility for the FLNP in a universal setting. However, low levels of exposure and contamination mean that uncertainty remains. TRIAL REGISTRATION: The trial is registered with Current Controlled Trials ISRCTN13919732.

International validation of the EORTC QLQ-ELD14 questionnaire for assessment of health-related quality of life elderly patients with cancer.

BACKGROUND: Older people represent the majority of cancer patients but their specific needs are often ignored in the development of health-related quality of life (HRQOL) instruments. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-ELD15 was developed to supplement the EORTC's core questionnaire, the QLQ-C30, for measuring HRQOL in patients aged >70 years in oncology studies. METHODS: Patients (n=518) from 10 countries completed the QLQ-C30, QLQ-ELD15 and a debriefing interview. Eighty two clinically stable patients repeated the questionnaires 1 week later (test-retest analysis) and 107 others, with an expected change in clinical status, repeated the questionnaires 3 months later (response to change analysis, RCA). RESULTS: Information from the debriefing interview, factor analysis and item response theory analysis resulted in the removal of one item (QLQ-ELD15QLQ-ELD14) and revision of the proposed scale structure to five scales (mobility, worries about others, future worries, maintaining purpose and illness burden) and two single items (joint stiffness and family support). Convergent validity was good. In known-group comparisons, the QLQ-ELD14 differentiated between patients with different disease stage, treatment intention, number of comorbidities, performance status and geriatric screening scores. Test-retest and RCA analyses were equivocal. CONCLUSION: The QLQ-ELD14 is a validated HRQOL questionnaire for cancer patients aged 70 years. Changes in elderly patients' self-reported HRQOL may be related to both cancer evolution and non-clinical events.

Quality of life in pulmonary surgery: choosing, using, and developing assessment tools.

There is mounting recognition that, to aid surgical decision making, treatment efficacy needs to be measured in a variety of ways, with health-related quality of life now widely regarded as an important outcome in pulmonary surgical populations. The aim of this review is to provide a comprehensive overview of the key issues to consider if an investigator wishes to incorporate health-related quality of life assessment into trials and studies of pulmonary surgery, drawing on recent studies of lung cancer surgery as an example.

Investigating CXCR4 expression in canine appendicular osteosarcoma.

BACKGROUND: Chemokine receptors (CXCRs) are transmembrane proteins classically studied for their participation in leukocyte homing. By their binding of cognate ligands, CXCRs orchestrate key cellular processes, including directional migration. Several different CXCRs are expressed on cancer cells and dictate tissue-specific metastases. In pediatric osteosarcoma (OSA), CXCR4 expression by tumor cells may participate in metastasis to tissues containing CXCL12, the partnering ligand for CXCR4. Canine and pediatric OSA share many biological similarities, including preferential metastasis to lung, bone, and lymph node. HYPOTHESIS: In canine immortalized cell lines and naturally occurring tumor samples, OSA cells will express CXCR4. In canine OSA cell lines, CXCR4 will participate in directional cell migration. METHODS: In vitro, CXCR4 expression in canine OSA cell lines was assessed by reverse-transcriptase polymerase chain reaction, Western blot analysis, flow cytometry, and immunocytochemistry. In vitro, involvement of CXCR4-mediated signaling for directional migration was investigated with a commercial assay. In vivo, CXCR4 expressions were evaluated in primary tumors and pulmonary metastases with immunocytochemistry and immunohistochemistry, respectively. RESULTS: In vitro, canine OSA cells express CXCR4 mRNA and protein. Ligation of CXCR4 with exogenous CXCL12 results in directional migration of canine OSA cell lines. In vivo, majority (8/11) of the canine OSA primary tumors, but minority (2/8) of the pulmonary metastases express CXCR4 protein. CONCLUSIONS AND CLINICAL IMPORTANCE: Canine OSA cells express CXCR4, and its signaling participates in directional migration. Most dogs with spontaneously arising OSA express CXCR4 within their primary tumors.

Trends in stomach and pancreatic cancer incidence and mortality in England and Wales, 1951-2000.

BACKGROUND: The aim of this study was to describe period and cohort effects in incidence and mortality of stomach and pancreatic cancer in England and Wales. METHODS: National figures for mortality (1951-2000) and incidence (1971-2000) were analysed using log-linear Poisson regression models to obtain relative risks (RR) for period (year of incidence or death) and cohort (year of birth). RESULTS: Stomach cancer shows a pronounced cohort effect in mortality with a decline in RR in men from 2.20 (1876) to 0.47 (1946) and a reduction from 2.79 to 0.41 for women. Mortality to incidence ratios are now less than 0.70. Pancreatic cancer mortality (men) RR rose from 0.91 (1951-1955) to a peak 1.11 (1976-1980) and then declined to 0.90 (1996-2000). Women showed a similar pattern. Cohort RR (men) increased to a peak of 1.14 in 1916 and declined to 1.01 in 1946, and continued to fall; the peak occurred slightly later in women. Mortality to incidence ratios were near 1 in the first 20 years, declining to 0.95 in the last 10 years. CONCLUSION: Stomach cancer incidence has fallen continuously from 19(th) century birth cohorts onwards. Incidence of pancreatic cancer has fallen in successive birth cohorts after 1920; peak period risk was 1976-1990. Age-standardized mortality and case mortality for pancreatic cancer are declining.

Is late diagnosis of lung cancer inevitable? Interview study of patients' recollections of symptoms before diagnosis.

BACKGROUND: A study was undertaken to explore the pathway to diagnosis among a group of patients recently diagnosed with lung cancer. METHODS: A directed interview study triangulating patients' accounts with hospital and GP records was performed with 22 men and women recently diagnosed with lung cancer at two cancer centres in the south and north of England. The main outcome measures were the symptoms leading up to a diagnosis of lung cancer and patient and GP responses before diagnosis. RESULTS: Patients recalled having new symptoms for many months, typically over the year before their diagnosis, irrespective of their disease stage once diagnosed. Chest symptoms (cough, breathing changes, and pain in the chest) were common, as were systemic symptoms (fatigue/lethargy, weight loss and eating changes). Although symptoms were reported as being marked changes in health, these were not in the main (with the exception of haemoptysis) interpreted as serious by patients at the time and not acted on. Once the trigger for action occurred (the event that took patients to their GP or elsewhere in the healthcare system), events were relatively speedy and were faster for patients who presented via their GP than via other routes. Patients' beliefs about health changes that may indicate lung cancer appeared to have played a part in delay in diagnosis. CONCLUSION: Further investigation of the factors influencing the timing of diagnosis in lung cancer is warranted since it appears that patients did not readily attend GP surgeries with symptoms. Insight into patients' perspectives on their experience before diagnosis may help medical carers to recognise patients with lung cancer more easily so that they can refer them for diagnosis and treatment. Encouragement to present early with signs of lung cancer should be considered alongside other efforts to speed up diagnosis and treatment.

What are we trying to measure? Rethinking approaches to health outcome assessment for the older person with cancer.

The health burden of cancer within the older population is well recognized. For many of these patients, interventions and treatments will focus predominantly on improvements in health outcomes. There has been substantial interest in the development and application of health outcome assessments for use in cancer patients, yet in comparison, there has been less focus on the older person with cancer. This paper will review current perspectives on health outcome assessment in older people with cancer; the methodological challenges associated with this work and present recommendations for future work, including the potential application of a 'user-generated' approach to health outcome assessment in the older person with cancer.

Highly conserved amino acids in Pax and Ets proteins are required for DNA binding and ternary complex assembly.

Combinatorial association of DNA-binding proteins on composite binding sites enhances their nucleotide sequence specificity and functional synergy. As a paradigm for these interactions, Pax-5 (BSAP) assembles ternary complexes with Ets proteins on the B cell-specific mb-1 promoter through interactions between their respective DNA-binding domains. Pax-5 recruits Ets-1 to bind the promoter, but not the closely related Ets protein SAP1a. Here we show that, while several different mutations increase binding of SAP1a to an optimized Ets binding site, only conversion of Val68 to an acidic amino acid facilitates ternary complex assembly with Pax-5 on the mb-1 promoter. This suggests that enhanced DNA binding by SAP1a is not sufficient for recruitment by Pax-5, but instead involves protein-protein interactions mediated by the acidic side chain. Recruitment of Ets proteins by Pax-5 requires Gln22 within the N-terminal beta-hairpin motif of its paired domain. The beta-hairpin also participates in recognition of a subset of Pax-5-binding sites. Thus, Pax-5 incorporates protein-protein interaction and DNA recognition functions in a single motif. The Caenorhabditis elegans Pax protein EGL-38 also binds specifically to the mb-1 promoter and recruits murine Ets-1 or the C.elegans Ets protein T08H4.3, but not the related LIN-1 protein. Together, our results define specific amino acid requirements for Pax-Ets ternary complex assembly and show that the mechanism is conserved between evolutionarily related proteins of diverse animal species. Moreover, the data suggest that interactions between Pax and Ets proteins are an important mechanism that regulates fundamental biological processes in worms and humans.

EGL-38 Pax regulates the ovo-related gene lin-48 during Caenorhabditis elegans organ development.

The Pax gene egl-38 plays an important role in the development of several organs in C. elegans. To understand how a Pax transcription factor influences distinct developmental choices in different cells and tissue types, we have characterized a second gene, lin-48. lin-48 functions with egl-38 in the development of one structure, the hindgut, but not in other tissues such as the egg-laying system. We show that lin-48 encodes a C2H2 zinc-finger protein that is similar to the product of the Drosophila gene ovo and is expressed in the hindgut cells that develop abnormally in lin-48 mutants. We present evidence that lin-48 is a target for EGL-38 in hindgut cells. We show that lin-48 requires egl-38 for its expression in the hindgut. Using deletion analysis, we have identified two elements in the lin-48 promoter that are necessary for lin-48 expression. We demonstrate that EGL-38 binds with high affinity to one of these elements. In addition, we have observed genetic interactions between mutations in the lin-48 promoter and specific alleles of egl-38. These experiments demonstrate a functional link between Pax and Ovo transcription factors, and provide a model for how Pax transcription factors can regulate different target genes in different cells.

Development of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the QLQ-C30 in patients with pancreatic cancer. EORTC Study Group on Quality of Life.

There is overwhelming consensus that quality of life assessment is urgently required in pancreatic cancer, yet little research has been conducted. We report on the development of a disease specific questionnaire module to supplement the EORTC core cancer module, the QLQ-C30 in patients with pancreatic cancer, using EORTC quality of life study group guidelines for module development. Relevant QoL issues were generated from literature searches and interviews with health professionals and patients with pancreatic cancer. Issues were constructed into items and provisionally translated. The provisional module was pretested in patients in 8 European centres. The resulting module the QLQ-PAN26 includes 26 items related to disease symptoms, treatment side-effects and emotional issues specific to pancreatic cancer. This should ensure that the module will be sensitive to assess the small but important disease and treatment related QoL changes in pancreatic cancer. The use of the QLQ-C30 and QLQ-PAN26 will provide a comprehensive system of QoL assessment in international trials of pancreatic cancer.

Differences in perception of quality of life issues between health professionals and patients with pancreatic cancer.

During the initial stages of development of a pancreatic cancer quality of life (QoL) module to supplement the EORTC core QoL module, the QLQ-C30, a qualitative study was undertaken to explore observed differences in the health professionals' and patients' perception of the illness, treatment and care of pancreatic cancer. Semi-structured one-to-one interviews were conducted with a range of six health professionals and 21 pancreatic cancer patients from two acute general hospitals and one teaching hospital within the Wessex Region. Grounded theory guided data collection and analysis. There was good agreement between the content of issues generated by professionals and patients with 42 relevant and specific issues identified. However, subtle differences in perception were observed when the context of why such issues were important was examined between the two groups. Health professionals took a mechanistic view and saw the impact of each symptom or problem as directly affecting quality of life perception. Patients' perception of quality of life was mediated by the process of coping. This was grounded by two linked factors. First, the perceived threat of each symptom or problem to the patient and second, the success or otherwise of coping strategies employed to maintain control. Five main coping strategies were identified. This study highlighted that there are important and specific quality of life issues which warrant a need for a pancreatic cancer QoL module. This study emphasises the fact that patients are the best source to describe their quality of life. Health professionals should acknowledge the effect of coping strategies when assessing the impact of symptoms and their treatment on patients with pancreatic cancer.