Randomised clinical trial: addition of alginate-antacid (Gaviscon Double Action) to proton pump inhibitor therapy in patients with breakthrough symptoms.

BACKGROUND: Symptomatic breakthrough in proton pump inhibitor (PPI)-treated gastro-oesophageal reflux disease (GERD) patients is a common problem with a range of underlying causes. The nonsystemic, raft-forming action of alginates may help resolve symptoms. AIM: To assess alginate-antacid (Gaviscon Double Action, RB, Slough, UK) as add-on therapy to once-daily PPI for suppression of breakthrough reflux symptoms. METHODS: In two randomised, double-blind studies (exploratory, n=52; confirmatory, n=262), patients taking standard-dose PPI who had breakthrough symptoms, assessed by Heartburn Reflux Dyspepsia Questionnaire (HRDQ), were randomised to add-on Gaviscon or placebo (20 mL after meals and bedtime). The exploratory study endpoint was change in HRDQ score during treatment vs run-in. The confirmatory study endpoint was "response" defined as ≥3 days reduction in the number of "bad" days (HRDQ [heartburn/regurgitation] >0.70) during treatment vs run-in. RESULTS: In the exploratory study, significantly greater reductions in HRDQ scores (heartburn/regurgitation) were observed in the Gaviscon vs placebo (least squares mean difference [95% CI] -2.10 [-3.71 to -0.48]; P=.012). Post hoc "responder" analysis of the exploratory study also revealed significantly more Gaviscon patients (75%) achieved ≥3 days reduction in "bad" days vs placebo patients (36%), P=.005. In the confirmatory study, symptomatic improvement was observed with add-on Gaviscon (51%) but there was no significant difference in response vs placebo (48%) (OR (95% CI) 1.15 (0.69-1.91), P=.5939). CONCLUSIONS: Adding Gaviscon to PPI reduced breakthrough GERD symptoms but a nearly equal response was observed for placebo. Response to intervention may vary according to whether symptoms are functional in origin.

A national survey of current practices of preparation and management of radical prostate radiotherapy patients during treatment.

AIMS: Radiotherapy is an important radical treatment for prostate cancer patients with services continually evolving. This survey aims to gain an insight in to the variation of radiotherapy practices in the UK, focussing on pre-treatment preparations, on-treatment review and management of radical prostate cancer patients undergoing radiotherapy. To our knowledge this is the first survey reported focussing on prostate radiotherapy practices with responses from a mix of health professionals. MATERIALS AND METHODS: A national survey was designed based on current known practices in supportive care and management of prostate cancer patients. The survey was distributed to lead radiotherapy personnel in radiotherapy services across the UK with a 77% response rate (n = 54). RESULTS: Pre-treatment protocols were mandated in the majority of departments. Use of bladder filling (98%) and bowel emptying (66%) were frequently deployed. Bowel preparation varied between use of laxatives (13%) or enemas (41%) to achieve consistency. On-treatment reviews were carried out by a mix of health professionals; most commonly shared between oncologists and radiographers (20%). Radiographers reviewing patients were independent prescribers in 22% of departments. Toxicity grading tools were not used by almost half of departments (47%) either at baseline and/or on-treatment reviews. Written information about follow-up was given to patients towards the end of their radiotherapy; however, fewer departments included the length of hormone duration (13%). CONCLUSION: This survey has demonstrated variations in practice exist across the UK. These variations suggest that important questions about the best methods for treatment accuracy and patient management need to be established through further research.

Co-enrolment of Participants into Multiple Cancer Trials: Benefits and Challenges.

Opportunities to enter patients into more than one clinical trial are not routinely considered in cancer research and experiences with co-enrolment are rarely reported. Potential benefits of allowing appropriate co-enrolment have been identified in other settings but there is a lack of evidence base or guidance to inform these decisions in oncology. Here, we discuss the benefits and challenges associated with co-enrolment based on experiences in the Add-Aspirin trial - a large, multicentre trial recruiting across a number of tumour types, where opportunities to co-enrol patients have been proactively explored and managed. The potential benefits of co-enrolment include: improving recruitment feasibility; increased opportunities for patients to participate in trials; and collection of robust data on combinations of interventions, which will ensure the ongoing relevance of individual trials and provide more cohesive evidence to guide the management of future patients. There are a number of perceived barriers to co-enrolment in terms of scientific, safety and ethical issues, which warrant consideration on a trial-by-trial basis. In many cases, any potential effect on the results of the trials will be negligible - limited by a number of factors, including the overlap in trial cohorts. Participant representatives stress the importance of autonomy to decide about trial enrolment, providing a compelling argument for offering co-enrolment where there are multiple trials that are relevant to a patient and no concerns regarding safety or the integrity of the trials. A number of measures are proposed for managing and monitoring co-enrolment. Ensuring acceptability to (potential) participants is paramount. Opportunities to enter patients into more than one cancer trial should be considered more routinely. Where planned and managed appropriately, co-enrolment can offer a number of benefits in terms of both scientific value and efficiency of study conduct, and will increase the opportunities for patients to participate in, and benefit from, clinical research.

Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis.

BACKGROUND: Metformin use has been associated with a reduced risk of developing cancer and an improvement in overall cancer survival rates in meta-analyses, but, to date, evidence to support the use of metformin as an adjuvant therapy in individual cancer types has not been presented. PATIENTS AND METHODS: We systematically searched research databases, conference abstracts and trial registries for any studies reporting cancer outcomes for individual tumour types in metformin users compared with non-users, and extracted data on patients with early-stage cancer. Studies were assessed for design and quality, and a meta-analysis was conducted to quantify the adjuvant effect of metformin on recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS), to inform future trial design. RESULTS: Of 7670 articles screened, 27 eligible studies were identified comprising 24 178 participants, all enrolled in observational studies. In those with early-stage colorectal cancer, metformin use was associated with a significant benefit in all outcomes [RFS hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.47-0.85; OS HR 0.69, CI 0.58-0.83; CSS HR 0.58, CI 0.39-0.86]. For men with early-stage prostate cancer, metformin was associated with significant, or borderline significant, benefits in all outcomes (RFS HR 0.83, CI 0.69-1.00; OS HR 0.82, CI 0.73-0.93; CSS HR 0.58, CI 0.37-0.93); however, there was significant heterogeneity between studies. The data suggest that prostate cancer patients treated with radical radiotherapy may benefit more from metformin (RFS HR 0.45, CI 0.29-0.70). In breast and urothelial cancer, no significant benefits were identified. Sufficient data were not available to conduct analyses on the impact of metformin dose and duration. CONCLUSIONS: Our findings suggest that metformin could be a useful adjuvant agent, with the greatest benefits seen in colorectal and prostate cancer, particularly in those receiving radical radiotherapy, and randomised, controlled trials which investigate dose and duration, alongside efficacy, are advocated.

Anticholinergic burden in schizophrenia and ability to benefit from psychosocial treatment programmes: a 3-year prospective cohort study.

BACKGROUND: Many medications administered to patients with schizophrenia possess anticholinergic properties. When aggregated, pharmacological treatments may result in a considerable anticholinergic burden. The extent to which anticholinergic burden has a deleterious effect on cognition and impairs ability to participate in and benefit from psychosocial treatments is unknown. METHOD: Seventy patients were followed for approximately 3 years. The MATRICS consensus cognitive battery (MCCB) was administered at baseline. Anticholinergic burden was measured with the Anticholinergic Cognitive Burden (ACB) scale. Ability to benefit from psychosocial programmes was measured using the DUNDRUM-3 Programme Completion Scale (D-3) at baseline and follow-up. Psychiatric symptoms were measured using the PANSS. Total antipsychotic dose was measured using chlorpromazine equivalents. Functioning was measured using the Social and Occupational Functioning Assessment Scale (SOFAS). RESULTS: Mediation analysis found that the influence of anticholinergic burden on ability to participate and benefit from psychosocial programmes was completely mediated by the MCCB. For every 1-unit increase on the ACB scale, change scores for DUNDRUM-3 decreased by -0.27 points. This relationship appears specific to anticholinergic burden and not total antipsychotic dose. Moreover, mediation appears to be specific to cognition and not psychopathology. Baseline functioning also acted as mediator but only when MCCB was not controlled for. CONCLUSIONS: Anticholinergic burden has a significant impact on patients' ability to participate in and benefit from psychosocial treatment programmes. Physicians need to be mindful of the cumulative effect that medications can have on patient cognition, functional capacity and ability to benefit from psychosocial treatments.

Do women who intermittently attend breast screening differ from those who attend every invitation and those who never attend?

OBJECTIVES: Analysis of screening uptake usually dichotomizes women into attenders and non-attenders, though many women respond positively to some but not all invitations. This paper studies these intermittent attenders. METHODS: A cohort of 8,571 women invited for consecutive breast screens in the Northern Ireland Breast Screening Programme were followed in a study linking screening and census records. Multivariate logistic analysis was used to analyze the characteristics of those who attended both times (consistent), once (intermittent or 'one-time only'), or not at all (non-attenders). RESULTS: Overall, 15.5% of women attended once and 13.4% were non-attenders. Non-attenders were characteristically disadvantaged (as measured by social renting, car access, and employment status), less likely to be married, and more likely to be healthy. One-time attenders were younger, and suffering poor health, though there was no association with either social renting or employment status. Privately rented accommodation and city living was associated with both one-time attendance and non-attendance. CONCLUSIONS: One-time attenders are an important and distinct subgroup of screening invitees in this analysis. Their distinct characteristics suggest that transitory factors, such as change in marital status, ill-health, or addressing difficulties through change of residence are important. These distinct characteristics suggest the need for different approaches to increase attendance, among both intermittent attenders and those not attending at all.

The efficacy of induction chemotherapy with docetaxel, cisplatin and 5-fluorouracil combined with cisplatin concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma: a matched pair analysis.

AIMS: The role of induction chemotherapy (ICT) for head and neck squamous cell carcinoma (HNSCC) is controversial. The aim of the study was to assess the benefit of ICT with docetaxel, cisplatin and 5-fluorouracil (5-FU) (TPF) when combined with concurrent cisplatin chemoradiotherapy (CRT) for HNSCC. MATERIALS AND METHODS: Patients with HNSCC treated between January 2005 and December 2010 with radical intent with either TPF or cisplatin and 5-FU (PF) ICT and documented intention to proceed with concurrent cisplatin CRT were identified retrospectively. The use and choice of ICT regimen was at the clinician's discretion. In total, 68 patients treated with TPF were identified and were matched for T and N stage and tumour site to 68 patients treated with PF. A survival analysis was carried out using Kaplan-Meier and the Cox proportional hazards model. RESULTS: The median follow-up was 29.9 versus 36.3 months for the TPF and PF groups, respectively. Three year locoregional relapse-free survival (RFS), distant RFS, RFS, cancer-specific survival and overall survival rates for the TPF and PF groups were 84.2, 91.6, 82.6, 81.3 and 74.9% versus 73.7, 84.9, 71.9, 72.1 and 62.9%, respectively. On multivariate analysis, treatment with TPF predicted for improved locoregional RFS (P = 0.03) and overall survival (P = 0.05). CONCLUSION: The addition of docetaxel to a cisplatin doublet ICT regimen before concurrent CRT may improve disease control for locally advanced HNSCC.

Breast cancer in older patients: national cancer registry data.

BACKGROUND: The population in developed countries is ageing. Cancer is a disease of ageing, and this is likely to lead to an increase in the number of older patients diagnosed with cancer with significant implications for resource allocation and research priorities. Breast Cancer in older women presents a number of challenges. AIMS: This paper describes the trends in number of new breast cancer registrations in older patients over the last 38 years. MATERIALS AND METHODS: Data were extracted from the Office for National Statistics describing new registrations of breast cancer for patients aged 65 or over, from 1971 to 2009. RESULTS: The number of diagnoses of breast cancer across all age groups increased from 17,694 in 1971 to 40,260 in 2009. The proportion of diagnoses of breast cancer made in women aged 65 and over increased from 42% in 1971 to 45% in 2009. The proportion of diagnoses of breast cancer made in women aged 70 and over increased from 30% in 1971 to 33% in 2009. The number of cases of breast cancer registered in patients aged 65 and over has increased from 7376 in 1971 to 17,934 in 2009. DISCUSSION: The reasons for the large increases in the number of older women diagnosed with breast cancer, and older women represent an increasing proportion of those diagnosed are multi-factorial. These include the ageing of the population, obesity, alcohol consumption, use of hormone replacement therapy and reproductive factors, improved breast cancer awareness and the UK National Screening Programme. Clinician attitudes and behaviours and also cancer registries striving to increase their levels are other causes. The effective management of these women will present constraints to service delivery and should therefore influence research priorities. CONCLUSION: This short communication reports on the increasing registration of breast cancer in the older age group which will present a number of challenges for the future.

Dentists' training and willingness to treat adolescents with learning disabilities: the mediating role of social and clinical factors.

AIM: To test a theoretical model based on Cohen's dental profession factors (training; practitioner attitudes; geography) to investigate practitioners' willingness to treat adolescents with learning disabilities (LD) in primary dental care. PARTICIPANTS: A sample of all 537 primary care dentists working in a mainly urban area of Northern Ireland and a more rural area of Scotland. MAIN OUTCOME MEASURE: Willingness to treat adolescents with LD. METHOD: Questionnaire survey of demographic profile, undergraduate education, current knowledge, attitudes towards individuals with LD and willingness to treat this patient group. A path analytical approach (multiple meditational model) was used. RESULTS: Three hundred dentists participated giving a valid response rate of 61%. Undergraduate education and current knowledge (training) strengthened a social model perspective promoting positive attitudes and willingness to treat adolescents with LD. Undergraduate education and current knowledge about disability did not significantly contribute to dentists whose attitudes were underpinned by the medical model of disability. Therefore geography (rural or urban location) was not an influential factor in willingness to treat adolescents with LD. This does not exclude the possibility that area of work may have an influence as a consequence of undergraduate university attended. CONCLUSION: This model identifies the importance of undergraduate and continuing dental education with regard to modifying professional attitudes (social and clinical factors) to assist practitioners treat adolescents with LD and provide them with inclusive dental services in primary dental care.

The role of split-course hypofractionated palliative radiotherapy in head and neck cancer.

AIMS: A significant proportion of patients with head and neck squamous cell carcinoma are unsuitable for radical treatment due to factors including tumour stage, performance status and co-morbidity. Palliative radiotherapy has a useful role in the control of local symptoms. This study documented the outcome with split-course hypofractionated radiotherapy. MATERIALS AND METHODS: Thirty-three previously untreated patients with head and neck squamous cell carcinoma were treated with palliative intent with split-course radiotherapy, with an initial 20 Gy in five fractions over 1 week, a 2 week gap, and then a further 20 Gy in five fractions over 1 week at the Yorkshire Cancer Centre between January 2004 and December 2007. Data were collected retrospectively from case notes and radiotherapy records. RESULTS: Thirty (91%) patients had stage IV A-B disease. World Health Organization performance status was 2 or 3 in 19 (58%) patients. The median age was 76 years (range 48-91 years). Twenty-five (76%) patients were men. Symptomatic improvement was reported in 26 (79%) patients at 4-6 weeks of follow-up. Thirteen (39%) patients had a complete tumour response and 11 (33%) patients had a partial response as assessed clinically, and in some cases radiologically. The median overall survival was 9 months (range 3-43 months). Progression-free survival at 1 and 2 years was 35 and 25%, respectively. Overall survival at 1 and 2 years was 42 and 34%, respectively. Treatment was generally well tolerated; admission for nasogastric feeding and/or supportive care was required in only six patients. Radiation Therapy Oncology Group grade 3 toxicity was documented for skin in one patient, for mucosa in two patients and for oesophagitis in three patients. CONCLUSION: Split-course hypofractionated radiotherapy is an effective palliative regimen with acceptable toxicity.

Induced abortion and intimate relationship quality in the Chicago Health and Social Life Survey.

OBJECTIVES: To examine associations between abortion and relationship functioning. STUDY DESIGN: Independent variables included abortion in a previous relationship and abortion in a current relationship. Perceptions of quality-of-life changes associated with terminating the relationship, conflict, aggressiveness and sexual dysfunction were the outcome measures. METHODS: Data were derived from interviews with an ethnically diverse urban sample of men (n=658) and women (n=906). Surveys were conducted in person using computer-assisted personal interview technology by the National Opinion Research Center affiliated with the University of Chicago, USA. RESULTS: For men and women, the experience of an abortion in a previous relationship was related to negative outcomes in the current relationship; perceptions of improved quality of life if the current relationship also ended and intimate partner violence. Experience of an abortion within a current relationship was associated with 116% and 196% increased risk of arguing about children for women and men, respectively. Among females, experience of an abortion within a current relationship was associated with increased risk for various forms of sexual dysfunction (122-182%), increased risk of arguments about money (75%), increased risk of conflict about the partner's relatives (80%), and increased risk of arguing about the respondent's relatives (99%). Men whose current partners had experienced an abortion were more likely to report jealousy (96% greater risk) and conflict about drugs (385% greater risk). CONCLUSION: Abortion may play a vital role in understanding the aetiology of relationship problems.

Herpes simplex virus vector-mediated delivery of neurturin rescues erectile dysfunction of cavernous nerve injury.

Neurturin (NTN), a member of glial cell line-derived neurotrophic factor (GDNF) family, is known as an important neurotrophic factor for penis-projecting neurons. We recently demonstrated significant protection from erectile dysfunction (ED) following a replication-defective herpes simplex virus (HSV) vector-mediated GDNF delivery to the injured cavernous nerve. Herein, we applied HSV vector-mediated delivery of NTN to this ED model. Rat cavernous nerve was injured bilaterally using a clamp and dry ice. For HSV-treated groups, 20 microl of vector stock was administered directly to the damaged nerve. Delivery of an HSV vector expressing both green fluorescent protein and lacZ (HSV-LacZ) was used as a control. Intracavernous pressure along with systemic arterial pressure (ICP/AP) was measured 2 and 4 weeks after the nerve injury. Fluorogold (FG) was injected into the penile crus 7 days before being killed to assess neuronal survival. Four weeks after nerve injury, rats treated with HSV-NTN exhibited significantly higher ICP/AP compared with untreated or control vector-treated groups. The HSV-NTN group had more FG-positive major pelvic ganglion neurons than the control group following injury. HSV vector-mediated delivery of NTN could be a viable approach for the improvement of ED following cavernous nerve injury.

The in vitro effects of bupivacaine on articular chondrocytes.

We have studied the effects of bupivacaine on human and bovine articular chondrocytes in vitro. Time-lapse confocal microscopy of human articular chondrocytes showed > 95% cellular death after exposure to 0.5% bupivacaine for 30 minutes. Human and bovine chondrocytes exposed to 0.25% bupivacaine had a time-dependent reduction in viability, with longer exposure times resulting in higher cytotoxicity. Cellular death continued even after removal of 0.25% bupivacaine. After exposure to 0.25% bupivacaine for 15 minutes, flow cytometry showed bovine chondrocyte viability to be 41% of saline control after seven days. After exposure to 0.125% bupivacaine for up to 60 minutes, the viability of both bovine and human chondrocytes was similar to that of control groups. These data show that prolonged exposure 0.5% and 0.25% bupivacaine solutions are potentially chondrotoxic.

Birth prevalence of cleft lip and palate in Northern Ireland (1981 to 2000).

OBJECTIVE: The prevalence of cleft lip and/or palate (CL/P) in Northern Ireland (NI) was last reported for 1980 through 1990. This study was undertaken to update the prevalence of CL/P in NI for the 20-year period 1981 to 2000, to determine the pattern of prevalence, and to report the proportion of different cleft types and sex distribution. DESIGN: Retrospective, population-based analysis. PATIENTS/PARTICIPANTS: All live born children with CL/P in NI from 1981 to 2000 were included. A total of 750 cases were identified. Resident births outside NI, stillbirths, abortuses, and children born with atypical orofacial clefts were excluded. Those with syndromes and submucous clefts were included in the study. RESULTS: The overall prevalence of children born with CL/P within NI for the period 1981 to 2000 was 1.47 per 1000 live births, or 1:682. This was consistent with the findings reported by other U.K. studies. There were no significant changes in the prevalence rates over any 5-year period. No significant seasonality trends were noted. Clefts of the palate only were always in the majority. More boys than girls were affected by cleft lip with or without cleft palate. There was a significant left-sided predilection for unilateral clefting of the lip. CONCLUSIONS: There have been no significant changes in the birth prevalence of children born with CL/P or the distribution or laterality of cleft type in the NI population during the past 20 years.

Salvaging locoregional recurrence with radiotherapy after surgery in early cervical cancer.

AIMS: To determine the outcome and morbidity after radiotherapy for locally recurrent cervical cancer. MATERIALS AND METHODS: Women who presented with locally recurrent cervical cancer after surgery alone during 1985 and 1997 were identified from the hospital database. Data were collected and analysed to include the stage at first diagnosis, staging investigations before surgery, the surgical procedure, the indication for radiotherapy, the type of radiotherapy, morbidity and survival. RESULTS: In total, 130 women had radical external beam radiotherapy and/or intracavitary brachytherapy for locoregional recurrence during the defined study period. The 5-year disease-specific survival for the study population was 40.2%. Women who were treated for vault recurrence had a significantly better 5-year disease-free survival compared with women who developed nodal recurrence alone (55.4% vs 12.5%). This group of women also had a significantly slower rate of disease progression after radiotherapy than women with nodal recurrence (48.7% vs 87.5%, P=0.0001). CONCLUSION: Radical radiotherapy alone is able to salvage 55% of vaginal vault recurrences after surgery for cervical cancer with minimal late toxicity. Salvage rates in women with pelvic nodal recurrences are considerably lower. Chemoradiotherapy using intensity-modulated radiotherapy to deliver an escalated radiotherapy dose needs to be pursued to improve locoregional control.