Embryonic vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes.

Environmental factors may alter the fetal genome to cause metabolic diseases. It is unknown whether embryonic immune cell programming impacts the risk of type 2 diabetes in later life. We demonstrate that transplantation of fetal hematopoietic stem cells (HSCs) made vitamin D deficient in utero induce diabetes in vitamin D-sufficient mice. Vitamin D deficiency epigenetically suppresses Jarid2 expression and activates the Mef2/PGC1a pathway in HSCs, which persists in recipient bone marrow, resulting in adipose macrophage infiltration. These macrophages secrete miR106-5p, which promotes adipose insulin resistance by repressing PIK3 catalytic and regulatory subunits and down-regulating AKT signaling. Vitamin D-deficient monocytes from human cord blood have comparable Jarid2/Mef2/PGC1a expression changes and secrete miR-106b-5p, causing adipocyte insulin resistance. These findings suggest that vitamin D deficiency during development has epigenetic consequences impacting the systemic metabolic milieu.

Specialist call handlers' perspectives on providing help on a cancer helpline: A qualitative interview study.

OBJECTIVE: To identify call handlers' key experiences of providing telephone help on a cancer helpline. METHODS: Semi-structured qualitative interviews with 30 call handlers from three UK-based cancer helplines. Transcribed interview data were analysed thematically. RESULTS: Thematic analysis identified three themes: (a) call handlers' perceptions of their role on the helpline, (b) challenges of working on a helpline and (c) the need for training/keeping up with competencies. Call handlers reported satisfaction with their experience. However, there are tensions: whilst advice is formally not part of the remit of the helpline, in practice the boundary between giving advice and giving information can be blurred. No follow-up with callers could be difficult and experienced as a lost opportunity to help. Managing patient expectations could be challenging, and interviewees described particular difficulties with distressed callers. Training for the role was commonplace, but there was sometimes a desire for more opportunities. CONCLUSION: There are challenges faced by helpline staff, and it can be difficult to manage callers' distress and expectations of what they might get from a call experience. Recognising the skill and complexity of the call handler role is important, as it is meeting call handlers' support and training needs. Support is important to minimise the risk to their own emotional well-being.

Clinical and patient-reported outcomes of SPARE - a randomised feasibility study of selective bladder preservation versus radical cystectomy.

OBJECTIVES: To test the feasibility of a randomised trial in muscle-invasive bladder cancer (MIBC) and compare outcomes in patients who receive neoadjuvant chemotherapy followed by radical cystectomy (RC) or selective bladder preservation (SBP), where definitive treatment [RC or radiotherapy (RT)] is determined by response to chemotherapy. PATIENTS AND METHODS: SPARE is a multicentre randomised controlled trial comparing RC and SBP in patients with MIBC staged T2-3 N0 M0, fit for both treatment strategies and receiving three cycles of neoadjuvant chemotherapy. Patients were randomised between RC and SBP before a cystoscopy after cycle three of neoadjuvant chemotherapy. Patients with ≤T1 residual tumour received a fourth cycle of neoadjuvant chemotherapy in both groups, followed by radical RT in the SBP group and RC in in the RC group; non-responders in both groups proceeded immediately to RC following cycle three. Feasibility study primary endpoints were accrual rate and compliance with assigned treatment strategy. The phase III trial was designed to demonstrate non-inferiority of SBP in terms of overall survival (OS) in patients whose tumours responded to neoadjuvant chemotherapy. Secondary endpoints included patient-reported quality of life, clinician assessed toxicity, loco-regional recurrence-free survival, and rate of salvage RC after SBP. RESULTS: Trial recruitment was challenging and below the predefined target with 45 patients recruited in 30 months (25 RC; 20 SBP). Non-compliance with assigned treatment strategy was frequent, six of the 25 patients (24%) randomised to RC received RT. Long-term bladder preservation rate was 11/15 (73%) in those who received RT per protocol. OS survival was not significantly different between groups. CONCLUSIONS: Randomising patients with MIBC between RC and SBP based on response to neoadjuvant chemotherapy was not feasible in the UK health system. Strong clinician and patient preferences for treatments impacted willingness to undergo randomisation and acceptance of treatment allocation. Due to the few participants, firm conclusions about disease and toxicity outcomes cannot be drawn.

A descriptive survey of cancer helplines in the United Kingdom: Who they are, the services offered, and the accessibility of those services.

BACKGROUND: There are more than 1500 UK health helplines in operation, yet we have scant knowledge about the resources in place to support the seeking and delivering of cancer-related telephone help and support. This research aimed to identify and describe cancer and cancer-related helpline service provision: the number of helplines available, the variety of services provided, and the accessibility of those services. METHOD: This study used online national questionnaire survey sent to 95 cancer and cancer-related helplines in the United Kingdom. RESULTS: A total of 69 (73%) of 95 surveyed cancer and cancer-related helplines completed the survey. Most helplines/organizations were registered charities, supported by donations; 73.5% of helplines had national coverage. Most helplines served all age-groups, ethnic groups, and men and women. Only 13.4% had a number that was free from landlines and most mobile networks, and 56.6% could only be contacted during working hours. More than 50% of helplines reported no provisions for callers with additional needs, and 55% had no clinical staff available to callers. Ongoing support and training for helpline staff was available but variable. CONCLUSION: Although cancer helplines in the United Kingdom offer reasonably broad coverage across the country, there are still potential barriers to accessibility. There are also opportunities to optimize the training of staff/volunteers across the sector. There are further prospects for helplines to enhance services and sustain appropriate and realistic quality standards.

Impact of Radiotherapy When Added to Androgen-Deprivation Therapy for Locally Advanced Prostate Cancer: Long-Term Quality-of-Life Outcomes From the NCIC CTG PR3/MRC PR07 Randomized Trial.

PURPOSE: The NCIC CTG PR3/MRC PR07 randomized phase III trial compared androgen-deprivation therapy (ADT) alone versus ADT with radiotherapy (RT) for patients with locally advanced prostate cancer. This article reports the health-related quality-of-life (HRQOL) outcomes of this trial. PATIENTS AND METHODS: A total of 1,205 patients were randomly allocated to either ADT alone or ADT with RT. HRQOL was assessed at baseline and every 6 months thereafter using the European Organisation for Research and Treatment of Cancer Core Questionnaire and a prostate cancer-specific checklist or the Functional Assessment of Cancer Therapy-Prostate questionnaire. Mean changes from baseline scores for five function domains and nine symptom domains were analyzed as those most relevant to ADT and RT. The proportions of patients with improved, stable, or worsened HRQOL scores according to instrument-specific minimal important differences were calculated. RESULTS: Baseline questionnaires were completed by 1,028 patients (88%). At 6 months, RT had a statistically significant impact on mean score for bowel symptoms (P = .02), diarrhea (P < .001), urinary function (P = .003), and erectile dysfunction (P = .008); by 3 years, however, there were no significant between-group differences in any domain. Generalized linear mixed modeling revealed no significant between-arm differences in any of the function scales but showed significant deterioration in both arms over time for Functional Assessment of Cancer Therapy-Prostate total score, treatment outcome index, and physical and functional well-being. CONCLUSION: The addition of RT to ADT for patients with locally advanced prostate cancer significantly improved overall survival and had only modest and transient negative impact on relevant domains of HRQOL.

The psychological impact of undergoing genetic-risk profiling in men with a family history of prostate cancer.

BACKGROUND: The ability to identify men at genetically high-risk of prostate cancer (PrCa) would enable screening to be targeted at those most in need. This study explored the psychological impact (in terms of general and PrCa-specific worry and risk perceptions) on men with a family history of PrCa, undergoing prostate screening and genetic-risk profiling, within a research study. METHODS: A prospective exploratory approach was adopted, incorporating a sequential mixed-method design. Questionnaires were completed at two time points to measure the impact of undergoing screening and genetic-risk profiling. In-depth interviews were completed in a subgroup after all study procedures were completed and analysed using a framework approach. RESULTS: Ninety-five men completed both questionnaires, and 26 were interviewed. No measurable psychological distress was detectable in the group as a whole. The interview findings fell into two categories: 'feeling at risk' and 'living with risk'. The feeling of being at risk of PrCa is a part of men's lives, shaped by assumptions and information gathered over many years. Men used this information to communicate about PrCa risk to their peers. Men overestimate their risk of PrCa and have an innate assumption that they will develop PrCa. The interviews revealed that men experienced acute anxiety when waiting for screening results. CONCLUSIONS: Personalised genetic-risk assessments do not prevent men from overestimating their risk of PrCa. Screening anxiety is common, and timeframes for receiving results should be kept to a minimum. Methods of risk communication in men at risk of PrCa should be the subject of future research.

"It's all very well reading the letters in the genome, but it's a long way to being able to write": Men's interpretations of undergoing genetic profiling to determine future risk of prostate cancer.

A family history of prostate cancer (PC) is one of the main risk factors for the disease. A number of common single nucleotide polymorphisms (SNPs) that confer small but cumulatively substantial risks of PC have been identified, opening the possibility for the use of SNPs in PC risk stratification for targeted screening and prevention in the future. The objective of this study was to explore the psychosocial impact of receiving information about genetic risk of PC. The participants were men who had a family history of PC and were enrolled in a screening study providing research genetic profiling alongside screening for PC. A combination of questionnaires and in-depth interviews were used. Questionnaires were completed by men at two time points: both before and after joining the study and going through the genetic profiling process. The interviews were completed after all study process were complete and were analysed using a framework analysis. In total 95 men completed both questionnaires and 26 men were interviewed. A number of issues facing men at risk of PC were identified. The results fell into two main categories: personal relevance and societal relevance. The strength of men's innate beliefs about their risk, shaped by genetic and environmental assumptions, outweigh the information provided by genetic testing. Men felt genetic profile results would have future use for accessing prostate screening, being aware of symptoms and in communicating with others. The findings reinforce the importance of providing contextual information alongside genetic profiling test results, and emphasises the importance of the counselling process in providing genetic risk information. This research raises some key issues to facilitate clinical practice and future research related to the use of genetic profiling to determine risk of PC and other diseases.

The role of helplines in cancer care: intertwining emotional support with information or advice-seeking needs.

Helplines are core feature of the contemporary U.K. health care system, however little is known about callers' experiences of seeking cancer-related telephone help. Qualitative interviews were conducted with 32 cancer helpline callers. The findings suggest cancer helplines offer callers (1) time to discuss their issues, (2) anonymity, (3) convenience, and (4) an open outlet for anyone affected by cancer including family/friends. Further, the findings highlighted that callers' help-seeking behavior was multifaceted, with their psychosocial needs being intrinsically intertwined with their information or advice-seeking needs. The implications are discussed in relation to the role of cancer helplines in the healthcare system.

25(OH) vitamin D suppresses macrophage adhesion and migration by downregulation of ER stress and scavenger receptor A1 in type 2 diabetes.

Cardiovascular disease (CVD) is the leading cause of mortality in patients with type 2 diabetes mellitus (T2DM). Vitamin D deficiency is not only more prevalent in diabetics but also doubles the risk of developing CVD. However, it is unknown whether 25-hydroxy vitamin D [25(OH)D3] replacement slows monocyte adhesion and migration, critical mechanisms involved in atherosclerosis progression. In this study, monocytes from vitamin D-deficient diabetic patients were cultured either in the patient's serum or in vitamin D-deficient media with or without 25(OH)D3 treatment. Adding 25(OH)D3 to monocytes cultured in vitamin D-deficient serum or media decreased monocyte adhesion to fibronectin and migration stimulated by monocyte chemotactic protein 1 (MCP-1). Accordingly, 25(OH)D3 decreased adhesion marker ß1- and ß2-integrin expression and migration receptor chemokine (C-C motif) receptor 2 (CCR2) expression. 25(OH)D3 treatment downregulated monocyte endoplasmic reticulum (ER) stress and scavenger receptor class A, type 1 (SR-A1) expression. The absence of SR-A1 prevented the increased macrophage adhesion and migration induced by vitamin D deficiency. Moreover, the absence of SR-A1 prevented the induction of adhesion and migration and expression of their associated membrane receptors by Thapsigargin, an ER stress inducer. These results identify cellular activation of monocyte/macrophage vitamin D signaling through 25(OH)D3 as a potential mechanism that could modulate adhesion and migration in diabetic subjects. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

The Patient Deficit Model Overturned: a qualitative study of patients' perceptions of invitation to participate in a randomized controlled trial comparing selective bladder preservation against surgery in muscle invasive bladder cancer (SPARE, CRUK/07/011).

BACKGROUND: Evidence suggests that poor recruitment into clinical trials rests on a patient 'deficit' model - an inability to comprehend trial processes. Poor communication has also been cited as a possible barrier to recruitment. A qualitative patient interview study was included within the feasibility stage of a phase III non-inferiority Randomized Controlled Trial (RCT) (SPARE, CRUK/07/011) in muscle invasive bladder cancer. The aim was to illuminate problems in the context of randomization. METHODS: The qualitative study used a 'Framework Analysis' that included 'constant comparison' in which semi-structured interviews are transcribed, analyzed, compared and contrasted both between and within transcripts. Three researchers coded and interpreted data. RESULTS: Twenty-four patients agreed to enter the interview study; 10 decliners of randomization and 14 accepters, of whom 2 subsequently declined their allocated treatment.The main theme applying to the majority of the sample was confusion and ambiguity. There was little indication that confusion directly impacted on decisions to enter the SPARE trial. However, confusion did appear to impact on ethical considerations surrounding 'informed consent', as well as cause a sense of alienation between patients and health personnel.Sub-optimal communication in many guises accounted for the confusion, together with the logistical elements of a trial that involved treatment options delivered in a number of geographical locations. CONCLUSIONS: These data highlight the difficulty of providing balanced and clear trial information within the UK health system, despite best intentions. Involvement of multiple professionals can impact on communication processes with patients who are considering participation in RCTs. Our results led us to question the 'deficit' model of patient behavior. It is suggested that health professionals might consider facilitating a context in which patients feel fully included in the trial enterprise and potentially consider alternatives to randomization where complex interventions are being tested. TRIAL REGISTRATION: ISRCTN61126465.

Attitudes to reproductive genetic testing in women who had a positive BRCA test before having children: a qualitative analysis.

The scope of conditions for which preimplantation genetic diagnosis (PGD) is licensed has recently been expanded in the United Kingdom to include genetic predisposition to adult-onset cancer. This qualitative interview study explores reproductive decision making, knowledge of and attitudes to reproductive genetic testing (prenatal diagnosis and PGD) with 25 women aged 18-45 years who received a positive BRCA test in the United Kingdom before having children. In this cohort of younger women, BRCA testing was motivated by risk management decisions; for some, BRCA status has affected their later decisions about having children. The perceived severity of hereditary breast/ovarian cancer (HBOC) influences thoughts about passing on the mutation to children and willingness to consider reproductive genetic testing, but most participants do not believe HBOC is a condition for which pregnancy termination is justified. PGD is considered more acceptable and advantageous because it would prevent transmission to future generations, but women have concerns about selecting embryos and the fact that they and affected family members would not have been selected. Women would also be deterred by the need to undergo in vitro fertilisation (IVF) and ovarian stimulation for PGD. Awareness of reproductive testing options was very variable among the cohort. The findings highlight the complexities of reproductive decision making for young women who knowingly carry a BRCA mutation, and the dilemmas inherent to reproductive genetic testing when the condition being tested for also affects a prospective parent. Counselling and psychological support for BRCA-positive women and couples concerning reproductive options are strongly indicated.

Information for decision making by patients with early-stage prostate cancer: a comparison across 9 countries.

PURPOSE: To describe decisional roles of patients with early-stage prostate cancer in 9 countries and to compare the information they rated important for decision making (DM). METHOD: A survey of recently treated patients was conducted in Canada, Italy, England, Germany, Poland, Portugal, Netherlands, Spain, and Turkey. Participants indicated their decisional role in their actual decision and the role they would prefer now. Each participant also rated (essential/desired/no opinion/avoid) the importance of obtaining answers, between diagnosis and treatment decision, to each of 92 questions. For each essential/desired question, participants specified all purposes for that information (to help them: understand/decide/plan/not sure/other). RESULTS: A total of 659 patients participated with country-specific response rates between 58%-77%. Between 83%-96% of each country's participants recalled actually taking an active decisional role and, in most countries, that increased slightly if they were to make the decision today; there were no significant differences among countries. There was a small reliable difference in the mean number of questions rated essential for DM across countries. More striking, however, was the wide variability within each country: no question was rated essential for DM by even 50% of its participants but almost every question was rated essential by some. CONCLUSIONS: Almost all participants from each country want to participate in their treatment decisions. Although there are country-specific differences in the amount of information required, wide variation within each country suggests that information that patients feel is essential or desired for DM should be addressed on an individual basis in all countries.

The requirements of a specialist Prostate Cancer Unit: a discussion paper from the European School of Oncology.

The widely recognised benefits of a multidisciplinary approach to treating cancer may be particularly important in prostate cancer, where there are so many treatment options to choose from. It offers patients the best chance of receiving high-quality medical procedures administered by a team of specialists in prostate disease, which is able to tailor treatment and observational strategies to their needs, and ensure access to specialist counselling, supportive care and rehabilitation. This article proposes Prostate Cancer Units as the most suitable structures for organising specialist multidisciplinary care for patients at all stages, from newly diagnosed to advanced disease, including preventing and managing the main complications, whether physical, emotional or psychological, arising from the disease and its treatment. Following the German example with prostate cancer, the British example with urological malignancies and the European breast cancer units, this article proposes general recommendations and mandatory requirements for Prostate Cancer Units, with a view to laying the basis for a network of certified units across Europe. Such a network could help improve standards of care throughout the region, providing patients, practitioners and health authorities with a means of identifying high-quality units and providing a system of quality control and audit. The article is intended as a contribution to the debate within the European uro-oncologic community on the best way to organise prostate cancer care.

Information needs of early-stage prostate cancer patients: a comparison of nine countries.

BACKGROUND AND PURPOSE: Providing information to patients can improve their medical and psychological outcomes. We sought to identify core information needs common to most early-stage prostate cancer patients in participating countries. MATERIAL AND METHODS: Convenience samples of patients treated 3-24 months earlier were surveyed in Canada, England, Italy, Germany, Poland, Portugal, Netherlands, Spain, and Turkey. Each participant rated the importance of addressing each of 92 questions in the diagnosis-to-treatment decision interval (essential/desired/no opinion/avoid). Multivariate modelling determined the extent of variance accounted by covariates, and produced an unbiased prediction of the proportion of essential responses for each question. RESULTS: Six hundred and fifty-nine patients responded (response rates 45-77%). On average, 35-53 questions were essential within each country; similar questions were essential to most patients in most countries. Beyond cross-country similarities, each country showed wide variability in the number and which questions were essential. Multivariate modelling showed an adjusted R-squared with predictors country, age, education, and treatment group of only 6% of the variance. A core of 20 questions were predicted to be essential to >2/3 of patients. CONCLUSIONS: Core information can be identified across countries. However, providing the core should only be a first step; each country should then provide information tailored to the needs of the individual patient.

Prospective study of factors predicting adherence to medical advice in men with testicular cancer.

PURPOSE: To identify predictive factors of adherence to medical advice, specifically the likelihood of attendance to a recommended follow-up regimen in patients with newly diagnosed testicular cancer. PATIENTS AND METHODS; This was a prospective study measuring initially not only aspects of the doctor-patient interview, but also a range of demographic, psychological, social, and medical factors, and then recording attendance behavior on follow-up. All 209 new patients with testicular cancer referred between June 1992 and May 1995 were approached, and 184 men consented and completed questionnaires. The nonadherence end point (nonattender) was two failures to attend an outpatient appointment at least 1 month apart, despite a written reminder. RESULTS: Thirty-two participants (17%) were classified as nonattenders. No significant differences were found between attenders and nonattenders in the majority of psychosocial and medical variables that might have predicted nonadherence to medical advice. There was a highly significant association between nonattendance and a patient's perception of an unsatisfactory affective relationship with his clinician (P = .005; hazard ratio, 3.1; 95% CI, 1.4 to 6.6). CONCLUSION: Patients who perceived an unsatisfactory affective relationship with their clinician that included an inability to trust the clinician and a perception that they were not being treated as "a person" were subsequently more likely to disregard medical advice regarding follow-up. Attention to the ways young men may wish to communicate with their clinicians is important, bearing in mind that they may not necessarily adhere to stereotypical images of masculine self-dependence.

Guilt, blame and responsibility: men's understanding of their role in the transmission of BRCA1/2 mutations within their family.

Men and women who have a family history of breast and/or ovarian cancer may be offered a predictive genetic test to determine whether or not they carry the family specific BRCA1/2 mutation. The sons and daughters of mutation carriers have a 50 per cent chance of inheriting a mutation, which will increase their risk of developing cancer. Little is known about at-risk men's feelings about the part they play in the transmission of BRCA1/2 mutations within their families. This study investigated high risk men's responses to BRCA1/2 predictive genetic testing. Seventeen in-depth interviews were undertaken with carrier (n= 5) and non-carrier men (n= 12). All men described genetic testing as a familial duty. It is observed that carriers and non-carriers mobilised differing explanations about their role in the aetiology of risk. It is noted that men engage in a form of narrative reconstruction in which they draw upon discourses of guilt and blame or fate and predestiny in an effort to present themselves as morally responsible or blameless. It is argued that narrative reconstruction enables these men to reconcile their genetic identity, self and family.

Prostate cancer patients' support and psychological care needs: Survey from a non-surgical oncology clinic.

While there are numerous uncertainties surrounding prostate cancer's detection and treatment, more research focusing on the psychological needs of prostate patients is required. This study investigated the support and psychological care needs of men with prostate cancer. Patients were approached during urological oncology clinics and asked to complete the: Support Care Needs Survey (SCNS), Support Care Preferences Questionnaire, EORTC QLQ-C30 (Version 3) Measure plus Prostate Module, and the Hospital Anxiety and Depression Scale (HADS). Of the 249 patients meeting study entry criteria, there was an 89% response rate resulting in a cohort of 210 patients. The data showed that significant unmet need exists across a number of domains in the areas of psychological and health system/information. The more commonly reported needs were 'fears about cancer spreading (44%),' 'concerns about the worries of those close to you (43%),' and 'changes in sexual feelings (41%).' Half of all patients reported some need in the domain of sexuality, especially men younger than 65 years. Needs were being well met in the domain of patient care and support. A significant number of patients reported having used or desiring support services, such as information about their illness, brochures about services and benefits for patients with cancer (55%), a series of talks by staff members about aspects of prostate cancer (44%), and one-on-one counselling (48%). Quality of life (QoL) was most negatively impacted in those who: were < or =65 years old, had been diagnosed within one year, or had metastatic disease. Men < or =65 had decreased social functioning, greater pain, increased sleep disturbance, and were more likely to be uncomfortable about being sexually intimate. Patients recently diagnosed had increased fatigue, more frequent urination, greater disturbance of sleep, and were more likely to have hot flushes. Those with advanced disease scored lower on 12 out of 15 QoL categories. PSA level had no effect on QoL or anxiety/depression scores. Men with advanced disease had greater levels of depression and those < or =65 years old were more likely to be anxious. Although most men with prostate cancer seem to function quite well, a substantial minority report areas of unmet need that may be targets for improving care.

Genetic testing for breast and ovarian cancer predisposition: cancer burden and responsibility.

The purpose of this study was to explore experiences of cancer in the family and motivation for predictive genetic testing among women at increased risk of developing breast and/or ovarian cancer due to their family history. Fifteen women were interviewed prior to receiving their genetic test results. A grounded theory approach was adopted to analyse the interview transcripts. The findings indicated that experiences of cancer in the family play an important role in formulating beliefs about one's own risk and motivation for predictive genetic testing. A sense of responsibility for one's own health and the need to take action either to prevent cancer or detect cancer at as early a stage as possible, as well as a feeling of responsibility towards children and other family members was apparent. The findings raise the question of whether there is any real choice available to these women and whether there is a negative impact on family dynamics.