Overexpression of Arginase 1 is linked to DNMT3A and TET2 mutations in lower-grade myelodysplastic syndromes and chronic myelomonocytic leukemia.

Immune dysregulation is a common feature of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), particularly in early stages. However, the genetic basis remains poorly understood. We recently reported that macrophages from mice deficient in tet methylcytosine dioxygenase 2 (Tet2), a model of MDS/CMML, are hyperinflammatory and have increased expression of arginase 1 (Arg1). In macrophages and myeloid derived suppressor cells (MDSCs) expression of Arg1 contributes to T-cell suppression and immune evasion by L-arginine depletion, in the setting of chronic inflammation and cancer. Since human MDS and CMML are driven by TET2 mutations and associated with chronic inflammation, we hypothesized that arginase enzymatic activity and ARG1 expression would be increased in human MDS/CMML bone marrow. Elevated arginase activity was observed in bone marrow mononuclear cells of MDS and CMML patients with lower-grade features. Immunohistochemical studies confirmed that myelomonocytic cells overexpress ARG1. Additionally, mutations in the epigenetic regulators TET2 and DNMT3A corresponded to high ARG1 expression and activity. These findings suggest ARG1 is a biomarker of immune dysregulation in early MDS and CMML. Recent murine findings have implicated Tet2 and Dnmt3a in regulation of innate immunity. Our study suggests similar changes may be driven by human TET2 and DNMT3A mutations.

Development and evaluation of a driving observation schedule (DOS) to study everyday driving performance of older drivers.

This paper describes the development and evaluation of an on-road procedure, the Driving Observation Schedule (DOS), for monitoring individual driving behavior. DOS was developed for use in the Candrive/Ozcandrive five-year prospective study of older drivers. Key features included observations in drivers' own vehicles, in familiar environments chosen by the driver, with start/end points at their own homes. Participants were 33 drivers aged 75+ years, who drove their selected route with observations recorded during intersection negotiation, lane-changing, merging, low speed maneuvers and maneuver-free driving. Driving behaviors were scored by a specialist occupational therapy driving assessor and another trained observer. Drivers also completed a post-drive survey about the acceptability of DOS. Vehicle position, speed, distance and specific roadways traveled were recorded by an in-vehicle device installed in the participant's vehicle; this device was also used to monitor participants' driving over several months, allowing comparison of DOS trips with their everyday driving. Inter-rater reliability and DOS feasibility, acceptability and ecological validity are reported here. On average, drivers completed the DOS trip in 30.48min (SD=7.99). Inter-rater reliability measures indicated strong agreement between the trained and the expert observers: intra-class correlations (ICC)=0.905, CI 95% 0.747-0.965, p<0.0001; Pearson product correlation, r (18)=.83, p<0.05. Standard error of the measurement (SEM), method error (ME) and coefficient of variation (CV) measures were consistently small (3.0, 2.9 & 3.3%, respectively). Most participants reported being 'completely at ease' (82%) with the driving task and 'highly familiar with the route' (97%). Vehicle data showed that DOS trips were similar to participants' everyday driving trips in roads used, roadway speed limits, drivers' average speed and speed limit compliance. In summary, preliminary findings suggest that DOS can be scored reliably, is of feasible duration, is acceptable to drivers and representative of everyday driving. Pending further research with a larger sample and other observers, DOS holds promise as a means of quantifying and monitoring changes in older drivers' performance in environments typical of their everyday driving.

Sci-Thur AM: Planning - 04: Evaluation of the fluence complexity, solution quality, and run efficiency produced by five fluence parameterizations implemented in PARETO multiobjective radiotherapy treatment planning software.

PURPOSE: PARETO (Pareto-Aware Radiotherapy Evolutionary Treatment Optimization) is a novel multiobjective treatment planning system that performs beam orientation and fluence optimization simultaneously using an advanced evolutionary algorithm. In order to reduce the number of parameters involved in this enormous search space, we present several methods for modeling the beam fluence. The parameterizations are compared using innovative tools that evaluate fluence complexity, solution quality, and run efficiency. METHODS: A PARETO run is performed using the basic weight (BW), linear gradient (LG), cosine transform (CT), beam group (BG), and isodose-projection (IP) methods for applying fluence modulation over the projection of the Planning Target Volume in the beam's-eye-view plane. The solutions of each run are non-dominated with respect to other trial solutions encountered during the run. However, to compare the solution quality of independent runs, each run competes against every other run in a round robin fashion. Score is assigned based on the fraction of solutions that survive when a tournament selection operator is applied to the solutions of the two competitors. To compare fluence complexity, a modulation index, fractal dimension, and image gradient entropy are calculated for the fluence maps of each optimal plan. RESULTS: We have found that the LG method results in superior solution quality for a spine phantom, lung patient, and cauda equina patient. The BG method produces solutions with the highest degree of fluence complexity. Most methods result in comparable run times. CONCLUSION: The LG method produces superior solution quality using a moderate degree of fluence modulation.

Development and evaluation of an instrument to assess social difficulties in routine oncology practice.

PURPOSE: To develop and preliminarily evaluate a Social Difficulties Inventory (SDI) for use in oncology practice. METHODS: Item generation from patients (n = 96), staff (n = 49) and the literature. Questions constructed and pre-tested (n = 42) resulting in a 22-item questionnaire. Psychometric evaluation (n = 271) assessed frequency of endorsement, factor structure, summated scales and construct validity followed by randomisation to criterion validity or test-retest arms. RESULTS: Items met preset frequency of endorsement criteria. Factor analysis revealed a four-factor structure, three clearly definable, (1) Physical ability, (2) Providing for the family and (3) Contact with others, explaining 45.8% variance. Summated scales developed from these demonstrated good reliability (Cronbach's alpha > 0.7) and were used to test and confirmed construct validity. Several comparators from the Life Events and Difficulties Schedule (LEDS) and Cancer Rehabilitation Evaluation System Short Form (CARES-SF) tested criterion validity and majority agreements were moderate to good. Test-retest reliability was good with most kappa values > 0.6. One item was eliminated resulting in a 21-item questionnaire. CONCLUSION: The SDI is relevant and easy to understand. Initial psychometric evaluation was encouraging. Ongoing work to evaluate the clinical meaning and utility of the instrument and to examine the relationships between SDI scores and clinical outcomes will provide guidance about its usefulness as an assessment tool in routine oncology practice.

Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules.

AIMS: To determine whether palliation of chest symptoms from a 10 Gy single fraction (regimen 1) was equivalent to that from 30 Gy in 10 fractions (regimen 2). MATERIALS AND METHODS: Patients with cytologically proven, symptomatic lung cancer not amenable to curative therapy, with performance status 0-3, were randomised to receive either 30 Gy in 10 fractions or a 10 Gy single fraction. Local symptoms were scored on a physician-assessed, five-point categorical scale and summed to produce a total symptom score (TSS). This, performance status, Hospital Anxiety and Depression (HAD) score and Spitzer's quality-of-life index were noted before treatment, at 1 month after treatment and every 2 months thereafter. Palliation was defined as an improvement of one point or more in the categorical scale. Equivalence was defined as less than 20% difference in the number achieving an improvement in the TSS. RESULTS: We randomised 149 patients and analysed 74 in each arm. According to the design criteria, palliation was equivalent between the two arms. TSS improved in 49 patients (77%) on regimen 1, and in 57 (92%) patients on regimen 2, a difference of 15% (95% confidence interval [CI] 3-28) in the proportion improving between the two regimens. A complete resolution of all symptoms was achieved in three (5%) on regimen 1, and in 14 (23%) patients on regimen 2 (P < 0.001), a difference in the proportion between the two regimens of 21% (95% CI 10-33). A significantly higher proportion of patients experienced palliation and complete resolution of chest pain and dyspnoea with regimen 2. No differences were observed in toxicity. The median survival was 22.7 weeks for regimen 1 and 28.3 weeks for regimen 2 (P = 0.197). CONCLUSIONS: Although this trial met the pre-determined criteria for equivalence between the two palliative regimens, significantly more patients achieved complete resolution of symptoms and palliation of chest pain and dyspnoea with the fractionated regimen.

A randomised comparison of UK genetic risk counselling services for familial cancer: psychosocial outcomes.

The aim of the study was to compare psychosocial outcomes for 50 new clinic attendees, referred for cancer genetic counselling to five UK centres. The centres represented England, Scotland and Wales, and were randomly selected from groups ranked by different levels of clinical activity in cancer genetics practice. Questionnaires assessed demographic data, risk perception, mental health and use of health services pre-consultation and at 1 and 12 months follow-up. Satisfaction was measured for attendees and referring doctors at follow-up. A total of 256 unaffected adults fulfilled the study criteria. The five centres varied widely with respect to service organisation and activity, but all had a greater proportion of unaffected attendees with a breast cancer risk (61-91%) than either a bowel cancer risk (0-33%) or ovarian cancer risk (3-25%). There were no significant differences in the psychosocial data between centres pre-counselling. No significant change over time occurred for any of the centres for risk perception or general psychological distress. There were significant differences between centres in reduction of cancer worry from baseline to 12 months and with the number of women who were recommended to have mammographic surveillance who had not received this. Overall, one-third of women for whom mammography had been recommended had not been screened within 1 year of follow-up. Subsequent attendance at the GP, but not at a hospital, was associated with risk level, but differences between centres could not be analysed. Satisfaction differed significantly between centres for 4 : 14 aspects of service provision and with 3 : 17 items concerning communication; satisfaction was high overall. Over 90% of referring doctors were moderately/very satisfied with the service, but 23% were dissatisfied with waiting times and 19% with access to preventive treatment. Results differed significantly between centres for doctor's satisfaction with the provision of referral criteria and prescribing information. In conclusion, there were relatively few significant differences in psychosocial outcomes between centres, considering the wide variation in service organisation and activity. These significant differences were not consistent across the centres, therefore, differences could not be linked to specific aspects of service provision.

Management of major depression in outpatients attending a cancer centre: a preliminary evaluation of a multicomponent cancer nurse-delivered intervention.

A novel nurse-delivered multicomponent intervention for major depressive disorder (MDD) in cancer outpatients was compared with usual care alone in a nonrandomised matched group design (n=30 per group). At the final 6-month outcome, 38.5% (95% CI, 5.4-57%) fewer patients in the intervention group still met the criteria for MDD.

Major depression in outpatients attending a regional cancer centre: screening and unmet treatment needs.

A screening programme designed to identify cases of Major Depressive Disorder (MDD) in patients attending a Regional Cancer Centre outpatient department was established. It comprised two stages: (1) The Hospital Anxiety and Depression Scale (HADS) self-rating questionnaire administered by a touch-screen computer; (2) we interviewed patients with high scores on the HADS (15 or more total score) over the telephone using the depression section of the Structured Clinical Interview for DSMIV (SCID). A large consecutive sample (5613) of oncology clinic attenders was screened, and practical difficulties in the screening process were identified. The estimated prevalence of major depressive disorder (MDD) in the sample surveyed was approximately 8% (7.8%; 95% confidence intervals 6.9-8.5%). We assessed a consecutive series of 150 patients identified as having MDD to determine how many had received evidence-based treatment for MDD. Only half had discussed their low mood with their general practitioner, only one-third had been prescribed any antidepressant medication, and very few had taken a therapeutic dose for an adequate period. Very few had received psychological treatment or had been referred to mental health services. Most were receiving no potentially effective therapy.

A randomised controlled trial of a psychoeducational intervention for women at increased risk of breast cancer.

This study aimed to compare the impact of two versions of a psychoeducational written intervention on cancer worry and objective knowledge of breast cancer risk-related topics in women who had been living with an increased risk of familial breast cancer for several years. Participants were randomised to three conditions: scientific and psychosocial information pack (Group 1), scientific information pack only (Group 2) or standard care control (Group 3). They completed postal questionnaires at baseline (n=163) and 4 weeks (n=151). As predicted, there was a significant decrease in cancer worry for Group 1, but not Group 2. Objective knowledge significantly improved for both Group 1 and Group 2 as expected, but not Group 3. However, there was an unpredicted decline in cancer worry for Group 3. This study supports the value of a scientific and psychosocial information pack in providing up-to-date information related to familial risk of breast cancer for long-term attendees of a familial breast cancer clinic. Further research is warranted to determine how the information pack could be incorporated into the existing clinical service, thus providing these women with the type of ongoing psychosocial support that many familial breast cancer clinics are currently lacking.

Is it acceptable to approach colorectal cancer patients at diagnosis to discuss genetic testing? A pilot study.

In this pilot study, the acceptability of approaching 111 newly diagnosed colorectal cancer patients with the offer of genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC) was assessed. A total of 78% of participants found it highly acceptable to have the information about HNPCC brought to their attention at that time.

A randomised controlled trial of breast cancer genetics services in South East Scotland: psychological impact.

This study compared the psychological impact of two models of breast cancer genetics services in South East Scotland. One hundred and seventy general practices were randomised to refer patients to the existing standard regional service or the novel community-based service. Participants completed postal questionnaires at baseline (n=373), 4 weeks (n=276) and 6 months (n=263) to assess perceived risk of breast cancer, subjective and objective understanding of genetics and screening issues, general psychological distress, cancer worry and health behaviours. For participants in both arms of the trial, there were improvements in subjective and objective understanding up to 4 weeks which were generally sustained up to 6 months. However, improvements in subjective understanding for the women at low risk of breast cancer (i.e. not at significantly increased risk) in the standard service arm did not reach statistical significance. Cancer worry was significantly reduced at 6 months for participants in both arms of the trial. The two models of cancer genetics services tested were generally comparable in terms of the participants' psychological outcomes. Therefore, decisions regarding the implementation of the novel community-based service should be based on the resources required and client satisfaction with the service.

An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-OV28) in assessing the quality of life of patients with ovarian cancer.

This study defines the psychometric properties of the European Organisation for Research and Treatment of Cancer (EORTC) quality of life (QOL) questionnaire designed to measure the QOL of patients with ovarian cancer. The ovarian cancer module (EORTC QLQ-OV28) was developed to supplement the EORTC QLQ-C30. The core questionnaire and the QLQ-OV28 were prospectively administered to 368 ovarian cancer patients after they had been treated with radical or debulking surgery followed by chemotherapy. The QLQ-OV28 module assesses abdominal/gastrointestinal symptoms, peripheral neuropathy, other chemotherapy side-effects, hormonal/menopausal symptoms, body image, attitude to disease/treatment and sexual functioning. Questionnaires were well accepted by patients, baseline compliance rates were 86%, 72% provided a second assessment, less than 3% of the items had missing data. Multi-trait scaling analyses confirmed the hypothesised scales. All hypothesised scales exhibited good psychometric properties. These results support the clinical and psychometric validity of the EORTC QLQ-OV28 module as a supplement to the EORTC QLQ-C30.

Feasibility and compliance of automated measurement of quality of life in oncology practice.

PURPOSE: Systematic quality-of-life (QOL) assessment may have value in oncology practice by increasing awareness of a wide range of issues, possibly increasing detection of psychologic morbidity, social problems, and changes in physical status, and improving care and its outcomes. However, logistic problems are substantial. Automated systems solve many of these problems. We field-tested the feasibility and compliance that can be achieved using a computer touchscreen system in two consecutive studies. PATIENTS AND METHODS: In study 1, a prospective cohort of 272 patients was offered QOL assessment at each clinic appointment for 6 months. In study 2, all patients (N = 1,291) were offered QOL assessment as part of clinic routine during a 12-week period. RESULTS: In study 1, 82% of patients agreed to take part, but over time, compliance was poor (median, 40%; mean, 43%) and deteriorated with longer follow-up. In study 2, the overall compliance was greatly increased (median, 100%; mean, 70%), and compliance was retained over multiple visits. In study 1, compliance was better in younger patients, males, and socially advantaged patients, but was not affected by the presence of depression or anxiety, or QOL. In the second study, building on experience in the first study, data collection and storage in the computer system was excellent, achieving 98% of collected data stored in one center. In general, patients were comfortable with the computers and the approach. Data collection on the wards was more difficult and less complete than in clinics, especially for patients undergoing acute admissions. CONCLUSION: Feasibility with higher compliance was demonstrated in study 2, in which the data collection was integrated into routine care, and can be improved with further technical initiatives and education of staff.

Social problems in oncology.

A study was undertaken to describe, evaluate and categorise the social problems experienced by cancer patients. Ninety-six adult cancer patients at all stages of disease participated in either a telephone focus group discussion, a face to face focus group or an individual interview which were tape recorded and transcribed. Six experts analysed the transcripts. A total of 32 social problems were identified categorized under eight headings plus four single items. The categories were: problems with (1) managing in the home, (2) health and welfare services, (3) finances, (4) employment, (5) legal matters, (6) relationships, (7) sexuality and body image and (8) recreation. Problems with relationships and communication were the most frequently reported with financial, employment, body image and domestic problems also being widely endorsed. Female groups, younger patient groups and groups where the aim of treatment was palliative reported more social problems than other groups. Social problems are common and important to cancer patients. The social problems identified in this study will contribute to an item pool generated for developing a Social Problems Inventory that may be included in patient centred assessment as part of routine oncology practice.

Validating automated screening for psychological distress by means of computer touchscreens for use in routine oncology practice.

The aim of the study was to confirm the validity of using touchscreen computers for screening for clinically significant levels of distress among cancer patients in routine oncology practice. The Hospital Anxiety and Depression Scale (HADS), EORTC Quality of Life questionnaire (QLQ-C30), Mental Health Inventory-MHI5 and a Concerns Checklist were administered via touchscreen computer to 172 chemotherapy out-patients, twice, 2-4 weeks apart. A standard psychiatric interview (Present State Examination - PSE) was conducted within a week of the second assessment. On interview, 23% of patients were identified as 'cases'. Using the available data (questionnaires, sociodemographic details, self-reported past psychiatric history), the best screening strategy combined scores from MHI-5 and HADS from a single time-point with the following rules: if MHI-5 < 11 = non-case; if MHI-5 > or = 11 then use HADS; then, if HADS > or = 9 = 'case' (sensitivity 85%; specificity 71%; misclassification rate 26%; positive predictive value 47%). The computerized screening system enabled data to be collected, scored, collated and reported in real time to identify patients who warrant further clinical assessment. It offers the potential for improving 'case' detection in routine oncology practice while reducing the burden of questions put to 'non-cases'. Further work is needed to develop optimal choice of screening questions for this purpose.

Deciding about prophylactic oophorectomy: what is important to women at increased risk of ovarian cancer?

BACKGROUND: Little is known about the factors that women at increased risk of ovarian cancer consider to be important when deciding about prophylactic oophorectomy, surgery to remove the ovaries before they develop cancer. METHODS: Women who had undergone prophylactic oophorectomy (surgical group; n = 30) were compared with women who remained on the ovarian screening program (nonsurgical group; n = 28) on their importance ratings for a number of relevant decision-making factors. RESULTS: The most important decision-making factor across all subjects was reducing risk of ovarian cancer, but the single best predictor of group membership was the importance attributed to reducing cancer worry. Women who rated this factor as more important were more likely to be in the surgical group. No women identified the increased risk of heart disease and osteoporosis as issues for consideration. CONCLUSIONS: The desire to reduce cancer worry is likely to be the most important factor in a woman's decision to proceed to prophylactic oophorectomy. In view of the current imprecision in risk estimates given to women considering this option, cancer worry may override a more rational consideration of the costs and benefits of surgery.

A descriptive study of UK cancer genetics services: an emerging clinical response to the new genetics.

The objective was to describe NHS cancer genetic counselling services and compare UK regions. The study design was a cross-sectional study over 4 weeks and attendee survey. The setting was 22 of the 24 regional cancer genetics services in the UK NHS. Participants were individuals aged over 18 attending clinics at these services. Outcome measures were staff levels, referral rates, consultation rates, follow-up plans, waiting time. There were only 11 dedicated cancer geneticists across the 22 centres. Referrals were mainly concerned with breast (63%), bowel (18%) and ovarian (12%) cancers. Only 7% of referrals were for men and 3% were for individuals from ethnic minorities. Referral rates varied from 76 to 410 per million per annum across the regions. Median waiting time for an initial appointment was 19 weeks, ranging across regions from 4 to 53 weeks. Individuals at population-level genetic risk accounted for 27% of consultations (range 0%, 58%). Shortfalls in cancer genetics staff and in the provision of genetic testing and cancer surveillance have resulted in large regional variations in access to care. Initiatives to disseminate referral and management guidelines to cancer units and primary care should be adequately resourced so that clinical genetics teams can focus on the genetic testing and management of high-risk families.

Prophylactic oophorectomy versus screening: psychosocial outcomes in women at increased risk of ovarian cancer.

This study investigated the psychosocial outcome of prophylactic oophorectomy versus regular screening in women at increased risk of ovarian cancer. Women who had undergone prophylactic oophorectomy (n=29) were compared with women who remained on the ovarian screening programme (n=28). Assessments were made retrospectively by postal questionnaire. The surgical group showed significantly poorer functioning on two sub-scales of the Short Form (SF)-36 Health Status Questionnaire (role-emotional (p=0.04) and social functioning (p=0.01)), and there was a trend (p=0.06) for them to report more menopausal symptoms. General Health Questionnaire (GHQ) scores were significantly higher (p=0.03) in the surgical group. There were no significant differences between the groups for cancer worry or sexual functioning. Experience of the operation was better (p=0.01) and incidence of self-reported post-operative problems was lower (p=0.02) for women who had undergone the 'keyhole' rather than an 'open' procedure. Being pre-menopausal at the time of surgery predicted higher GHQ (p=0.04) and longer subjective recovery time (p=0.04). Women who have undergone prophylactic oophorectomy may have more physical and emotional symptoms than women who remain on an ovarian cancer screening programme, and may report equivalent levels of cancer worry. Those who are pre-menopausal at the time of the operation may be particularly vulnerable to psychological distress and take longer to recover post-operatively. A larger prospective study is needed to evaluate the casual versus causal role of oophorectomy in these findings, and the extent to which it allays patients' fear of cancer.

Detecting social problems in cancer patients.

Diagnosis of and treatment for cancer may not only create physical and emotional difficulties for patients but may also have an impact on social aspects of patients' lives. Screening for social problems has not become part of routine oncology practice. This may be due to lack of a suitable questionnaire. This paper presents a psychometric analysis of the Problems Checklist with a view to assessing its usefulness as a screening tool for social problems in oncology. Evaluation was undertaken using data from an earlier study of 505 patients who completed the checklist. Frequency of endorsement, missing values, factor analysis and reliability and validity analysis of the summated scales were carried out. Missing data rates ranged from 4 to 18% over the 16 items. Fourteen items were well endorsed. Factor analysis produced a four-factor structure with components labelled daily living, relationships, economics and emotions. Reliability and validity tests endorsed the factor structure with the components on economics and emotions being particularly credible. Difficulties with relationships are harder to measure and results from the analysis suggest that this is an area that warrants further investigation. The checklist is a useful tool for highlighting problems. As a tool for screening for social problems it has some limitations.

A family history of breast cancer: women's experiences from a theoretical perspective.

Individuals at increased risk of developing breast cancer due to their family history of the disease face a number of uncertainties. Personal cancer risk estimates are imprecise and current methods for early detection or prevention are not 100% effective. It is therefore not surprising that adverse psychosocial outcomes have been described within this population. Research attempting to predict the incidence of distress and dysfunction in individuals at increased risk of cancer has been largely a-theoretical and has overlooked a number of potentially important predictive variables. In particular, the influence of personal experience of cancer through involvement with affected relatives has been neglected. There are strong theoretical grounds for hypothesising that dimensions of personal experience may influence response to cancer risk. This paper discusses the potential impact of personal experience on risk perception, illness representations and decision-making. Systematic research in this area may improve predictions of outcome of cancer genetic counselling and inform the clinical process.