Recurrence of vulval intraepithelial neoplasia following treatment with cidofovir or imiquimod: results from a multicentre, randomised, phase II trial (RT3VIN).

OBJECTIVE: To compare the recurrence rates after complete response to topical treatment with either cidofovir or imiquimod for vulval intraepithelial neoplasia (VIN) 3. DESIGN: A prospective, open, randomised multicentre trial. SETTING: 32 general hospitals located in Wales and England. POPULATION OR SAMPLE: 180 patients were randomised consecutively between 21 October 2009 and 11 January 2013, 89 to cidofoovir (of whom 41 completely responded to treatment) and 91 to imiquimod (of whom 42 completely responded to treatment). METHODS: After 24 weeks of treatment, complete responders were followed up at 6-monthly intervals for 24 months. At each visit, the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 was assessed and any new lesions were biopsied for histology. MAIN OUTCOME MEASURES: Time to histologically confirmed disease recurrence (any grade of VIN). RESULTS: The median length of follow up was 18.4 months. At 18 months, more participants were VIN-free in the cidofovir arm: 94% (95% CI 78.2-98.5) versus 71.6% (95% CI 52.0-84.3) [univariable hazard ratio (HR) 3.46, 95% CI 0.95-12.60, P = 0.059; multivariable HR 3.53, 95% CI 0.96-12.98, P = 0.057). The number of grade 2+ events was similar between treatment arms (imiquimod: 24/42 (57%) versus cidofovir: 27/41 (66%), χ2 = 0.665, P = 0.415), with no grade 4+. CONCLUSIONS: Long-term data indicates a trend towards response being maintained for longer following treatment with cidofovir than with imiquimod, with similar low rates of adverse events for each drug. Adverse event rates indicated acceptable safety of both drugs TWEETABLE ABSTRACT: Long-term follow up in the RT3VIN trial suggests cidofovir may maintain response for longer than imiquimod.

Long-term results and recurrence patterns from SCALOP: a phase II randomised trial of gemcitabine- or capecitabine-based chemoradiation for locally advanced pancreatic cancer.

BACKGROUND: SCALOP, a randomised, phase II trial, tested the activity and safety of gemcitabine (GEM)-based and capecitabine (CAP)-based chemoradiation (CRT) for locally advanced pancreatic cancer (LAPC). Here we present the long-term outcomes. METHODS: Eligibility: histologically proven LAPC ⩽7 cm. Following 12 weeks of induction GEMCAP chemotherapy (three cycles: GEM 1000 mg m-2 days 1, 8, 15; CAP 830 mg m-2 days 1-21 q28 days) patients with stable/responding disease, tumour ⩽6 cm, and WHO Performance Status 0-1 were randomised to receive one cycle GEMCAP followed by CAP (830 mg m-2 b.d. on weekdays only) or GEM (300 mg m-2 weekly) with radiation (50.4 Gy per 28 fractions). RESULTS: One-hundred fourteen patients (28 UK centres) were registered between 24 December 2009 and 25 October 2011, and 74 were randomised (CAP-RT=36; GEM-RT=38). At the time of this analysis, 105 of the 114 patients had died and the surviving 9 patients had been followed up for a median of 10.9 months (IQR: 2.9-18.7). Updated median OS was 17.6 months (95% CI: 14.6-22.7) in the CAP-CRT arm and 14.6 months (95% CI: 11.1-16.0) in the GEM-CRT arm (intention-to-treat adjusted hazard ratio (HR): 0.68 (95% CI: 0.38-1.21, P=0.185)); median progression-free survival (PFS) was 12.0 months (95% CI: 10.0-15.2) in the CAP-CRT arm and 10.4 months (95% CI: 8.8-12.7) in the GEM-CRT arm (intention-to-treat adjusted HR: 0.60 (95% CI: 0.32-1.14, P=0.120)). In baseline multivariable model, age ⩾65 years, better performance status, CA19.9<613 IU l-1, and shorter tumour diameter predicted improved OS. CAP-CRT, age ⩾65 years, better performance status, CA19.9 <46 IU ml-1 predicted improved OS and PFS in the pre-radiotherapy model. Nine-month PFS was highly predictive of OS. CONCLUSIONS: CAP-CRT remains the superior regimen. SCALOP showed that patients with CA19.9 <46 IU ml-1 after induction chemotherapy are more likely to benefit from CRT.

Long-term results and recurrence patterns from SCOPE-1: a phase II/III randomised trial of definitive chemoradiotherapy +/- cetuximab in oesophageal cancer.

BACKGROUND: The SCOPE-1 study tested the role of adding cetuximab to conventional definitive chemoradiotherapy (dCRT), and demonstrated greater toxicity and worse survival outcomes. We present the long-term outcomes and patterns of recurrence. METHODS: SCOPE-1 was a phase II/III trial in which patients were randomised to cisplatin 60 mg m-2 (day 1) and capecitabine 625 mg m-2 bd (days 1-21) for four cycles +/- cetuximab 400 mg m-2 day 1 then by 250 mg m-2 weekly. Radiotherapy consisted of 50 Gy/25# given concurrently with cycles 3 and 4. Recruitment was between February 2008 and February 2012, when the IDMC recommended closure on the basis of futility. RESULTS: About 258 patients (dCRT=129; dCRT+cetuximab (dCRT+C)=129) were recruited from 36 centres. About 72.9% (n=188) had squamous cell histology. The median follow-up (IQR) was 46.2 (35.9-48.3) months for surviving patients. The median overall survival (OS; months; 95% CI) was 34.5 (24.7-42.3) in dCRT and 24.7 (18.6-31.3) in dCRT+C (hazard ratio (HR)=1.25, 95% CIs: 0.93-1.69, P=0.137). Median progression-free survival (PFS; months; 95% CI) was 24.1 (15.3-29.9) and 15.9 (10.7-20.8) months, respectively (HR=1.28, 95% CIs: 0.94-1.75; P=0.114). On multivariable analysis only earlier stage, full-dose RT, and higher cisplatin dose intensity were associated with improved OS. CONCLUSIONS: The mature analysis demonstrates that the dCRT regimen used in the study provided useful survival outcomes despite its use in patients who were largely unfit for surgery or who had inoperable disease. Given the competing risk of systemic and local failure, future studies should continue to focus on enhancing local control as well as optimising systemic therapy.

Role of nutritional status and intervention in oesophageal cancer treated with definitive chemoradiotherapy: outcomes from SCOPE1.

BACKGROUND: Malnutrition is common in oesophageal cancer. We aimed to identify nutritional prognostic factors and survival outcomes associated with nutritional intervention in the SCOPE1 (Study of Chemoradiotherapy in OesoPhageal Cancer with or without Erbitux) trial. METHODS: Two hundred and fifty eight patients were randomly allocated to definitive chemoradiotherapy (dCRT) +/- cetuximab. Nutritional Risk Index (NRI) scores were calculated; NRI<100 identified patients at risk of malnutrition. Nutritional intervention included dietary advice, oral supplementation or major intervention (enteral feeding/tube placement). Univariable and multivariable analyses using Cox proportional hazard modelling were conducted. RESULTS: At baseline NRI<100 strongly predicted for reduced overall survival (hazard ratio (HR) 12.45, 95% CI 5.24-29.57; P<0.001). Nutritional intervention improved survival if provided at baseline (dietary advice (HR 0.12, P=0.004), oral supplementation (HR 0.13, P<0.001) or major intervention (HR 0.13, P=0.003)), but not if provided later in the treatment course. Cetuximab patients receiving major nutritional intervention had worse outcomes compared with controls (13 vs 28 months, P=0.003). CONCLUSIONS: Pre-treatment assessment and correction of malnutrition may improve survival outcomes in oesophageal cancer patients treated with dCRT. Nutritional Risk Index is a simple and objective screening tool to identify patients at risk of malnutrition.

Anxiety and anxious-depression in Parkinson's disease over a 4-year period: a latent transition analysis.

BACKGROUND: Depression and anxiety in Parkinson's disease are common and frequently co-morbid, with significant impact on health outcome. Nevertheless, management is complex and often suboptimal. The existence of clinical subtypes would support stratified approaches in both research and treatment. METHOD: Five hundred and thirteen patients with Parkinson's disease were assessed annually for up to 4 years. Latent transition analysis (LTA) was used to identify classes that may conform to clinically meaningful subgroups, transitions between those classes over time, and baseline clinical and demographic features that predict common trajectories. RESULTS: In total, 64.1% of the sample remained in the study at year 4. LTA identified four classes, a 'Psychologically healthy' class (approximately 50%), and three classes associated with psychological distress: one with moderate anxiety alone (approximately 20%), and two with moderate levels of depression plus moderate or severe anxiety. Class membership tended to be stable across years, with only about 15% of individuals transitioning between the healthy class and one of the distress classes. Stable distress was predicted by higher baseline depression and psychiatric history and younger age of onset of Parkinson's disease. Those with younger age of onset were also more likely to become distressed over the course of the study. CONCLUSIONS: Psychopathology was characterized by relatively stable anxiety or anxious-depression over the 4-year period. Anxiety, with or without depression, appears to be the prominent psychopathological phenotype in Parkinson's disease suggesting a pressing need to understanding its mechanisms and improve management.

Patient-reported outcomes during and after definitive chemoradiotherapy for oesophageal cancer.

BACKGROUND: Limited data describe patient-reported outcomes (PROs) of localised oesophageal cancer treated with definitive chemoradiotherapy(CRT). The phase 2/3 SCOPE-1 trial assessed the effectiveness of CRT±cetuximab. The trial for the first time provided an opportunity to describe PROs from a multi-centre group of patients treated with CRT that are presented here. METHODS: Patients undergoing CRT±cetuximab within the SCOPE-1 trial (258 patients from 36 UK centres) completed generic-, disease- and treatment-specific health-related quality of life (HRQL) questionnaires (EORTC QLQ-C30, QLQ-OES18, Dermatology Life-Quality Index (DLQI)) at baseline and at 7, 13, 24, 52 and 104 weeks. Mean EORTC functional scale scores (>15 point change significant), DLQI scores (>4 point change significant) and proportions of patients (>15% significant) with 'minimal' or 'severe' symptoms are presented. RESULTS: Questionnaire response rates were good. At baseline, EORTC functional scores were high (>75%) and few symptoms were reported except for severe problems with fatigue, insomnia and eating-related symptoms (e.g., appetite loss, dysphagia, dry mouth) in both groups(>15%). Functional aspects of health deteriorated and symptoms increased with treatment and by week 13 global quality of life, physical, role and social function significantly deteriorated and more problems with fatigue, dyspnoea, appetite loss and trouble with taste were reported. Recovery occurred by 6 months (except severe fatigue and insomnia in >15% of patients) and maintained at follow-up with no differences between groups. CONCLUSIONS: CRT for localised oesophageal cancer has a significant detrimental impact on many aspects of HRQL; however, recovery is achieved by 6 months and maintained with the exception of persisting problems with severe fatigue and insomnia. The data suggest that the HRQL recovery after definitive CRT is quicker, and there is little lasting deficit compared with treatment including surgery. These data need to be compared with HRQL data from studies evaluating treatments including surgery for oesophageal cancer.

Ecological speciation in anemone-associated snapping shrimps (Alpheus armatus species complex).

Divergent natural selection driven by competition for limited resources can promote speciation, even in the presence of gene flow. Reproductive isolation is more likely to result from divergent selection when the partitioned resource is closely linked to mating. Obligate symbiosis and host fidelity (mating on or near the host) can provide this link, creating ideal conditions for speciation in the absence of physical barriers to dispersal. Symbiotic organisms often experience competition for hosts, and host fidelity ensures that divergent selection for a specific host or host habitat can lead to speciation and strengthen pre-existing reproductive barriers. Here, we present evidence that diversification of a sympatric species complex occurred despite the potential for gene flow and that partitioning of host resources (both by species and by host habitat) has contributed to this diversification. Four species of snapping shrimps (Alpheus armatus, A. immaculatus, A. polystictus and A. roquensis) are distributed mainly sympatrically in the Caribbean, while the fifth species (A. rudolphi) is restricted to Brazil. All five species are obligate commensals of sea anemones with a high degree of fidelity and ecological specificity for host species and habitat. We analysed sequence data from 10 nuclear genes and the mitochondrial COI gene in 11-16 individuals from each of the Caribbean taxa and from the only available specimen of the Brazilian taxon. Phylogenetic analyses support morphology-based species assignments and a well-supported Caribbean clade. The Brazilian A. rudolphi is recovered as an outgroup to the Caribbean taxa. Isolation-migration coalescent analysis provides evidence for historical gene flow among sympatric sister species. Our data suggest that both selection for a novel host and selection for host microhabitat may have promoted diversification of this complex despite gene flow.

Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson's disease: a longitudinal 4-year study.

OBJECTIVE: To examine the prevalence, incidence and risk factors associated with visual hallucinations (VHs) amongst people suffering from Parkinson's disease (PD). METHODS: We recruited 513 patients with PD from movement disorder and PD clinics within three sites in the UK. Patients were interviewed using a series of standardised clinical rating scales at baseline, 12, 24 and 36 months. Data relating to VHs were collected using the North-East Visual Hallucinations Interview. Prevalence rates for VHs at each assessment were recorded. Associations were determined using multiple regression analysis. RESULTS: Cross-sectional prevalence rates for VHs at baseline, 12, 24 and 36 months indicated VHs in approximately 50% of patients. A cumulative frequency of 82.7% of cases at the end of the study period exhibited VHs. The incidence rate for VHs was 457 cases per 1000 population. Longer disease duration, greater impairment in activities of daily living and higher rates of anxiety were most commonly associated with VHs. No factors predictive of VHs could be ascertained. CONCLUSIONS: When examined longitudinally, VHs affect more patients than is commonly assumed in cross-sectional prevalence studies. Clinicians should routinely screen for VHs throughout the disease course. Disease duration, impairment in activities of daily living and anxiety presented as co-morbidities associated with VHs in PD, and therefore those presenting with VHs should be screened for anxiety disorder and vice versa.

Are women ready for the new cervical screening protocol in England? A systematic review and qualitative synthesis of views about human papillomavirus testing.

BACKGROUND: A new protocol for human papillomavirus (HPV) testing within the UK cervical screening programme commenced in April 2011, creating new patient experiences. This is the first review to synthesise a substantial body of international evidence of women's information needs, views and preferences regarding HPV testing. We aimed to inform the development of educational materials to promote informed choice, reduce anxiety and improve disease control. METHODS: We searched 12 bibliographic databases. Two reviewers independently screened papers and assessed study quality; disagreements were resolved by discussion. Results were extracted verbatim and authors' findings treated as primary data. Studies were synthesised collaboratively using framework methods. RESULTS: We synthesised findings from 17 studies. Women had overwhelmingly negative concerns; an HPV diagnosis was daunting, had associated problems of disclosure of a sexually transmitted infection (STI), impacted on relationships and provoked fear of stigmatisation. Nevertheless, many thought HPV testing could be a preferable alternative to repeat cytology. Knowledge was poor; women struggled to interpret limited information in the context of existing knowledge about STIs and cervical cancer. CONCLUSION: Women are likely to be poorly informed, have limited understanding and many unanswered questions. This could increase anxiety and reduce ability to make informed choices, presenting a substantial challenge for those who design and provide information.

Frontotemporal atrophy associated with paranoid delusions in women with Alzheimer's disease.

BACKGROUND: Paranoid delusions are a common and difficult-to-manage feature of Alzheimer's disease (AD). We investigated the neuroanatomical correlates of paranoid delusions in a cohort of AD patients, using magnetic resonance imaging (MRI) to measure regional volume and regional cortical thickness. METHODS: 113 participants with probable AD were assessed for severity of disease, cognitive and functional impairment. Presence and type of delusions were assessed using the Neuropsychiatric Inventory (NPI). Structural MRI images were acquired on a 1.5 T scanner, and were analyzed using an automated analysis pipeline. RESULTS: Paranoid delusions were experienced by 23 (20.4%) of the participants. Female participants with paranoid delusions showed reduced cortical thickness in left medial orbitofrontal and left superior temporal regions, independently of cognitive decline. Male participants with delusions did not show any significant differences compared to males without delusions. An exploratory whole brain analysis of non-hypothesized regions showed reduced cortical thickness in the left insula for female participants only. CONCLUSION: Frontotemporal atrophy is associated with paranoid delusions in females with AD. Evidence of sex differences in the neuroanatomical correlates of delusions as well as differences in regional involvement in different types of delusions may be informative in guiding management and treatment of delusions in AD.

SCOPE 2 - Still Answering the Unanswered Questions in Oesophageal Radiotherapy? SCOPE 2: a Randomised Phase II/III Trial to Study Radiotherapy Dose Escalation in Patients with Oesophageal Cancer Treated with Definitive Chemoradiation with an Embedded Phase II Trial for Patients with a Poor Early Response using Positron Emission Tomography/Computed Tomography.

The SCOPE 2 trial of definitive chemoradiotherapy in oesophageal cancer investigates the benefits of radiotherapy dose escalation and systemic therapy optimisation. The trial opened in 2016. The landscape of oesophageal cancer treatment over the lifetime of this trial has changed significantly and the protocol has evolved to reflect this. However, with the recent results of the Dutch phase III ART DECO study showing no improvement in local control or overall survival with radiotherapy dose escalation in a similar patient group, we sought to determine if the SCOPE 2 trial is still answering the key unanswered questions for oesophageal radiotherapy. Here we discuss the rationale behind the SCOPE 2 trial, outline the trial schema and review current data on dose escalation and outline recommendations for future areas of research.

Coping in Parkinson's disease: an examination of the coping inventory for stressful situations.

BACKGROUND: Parkinson's disease (PD) brings with it a range of stresses and challenges with which a patient must cope. The type of coping strategies employed can impact upon well-being, although findings from coping studies in PD remain inconsistent. The variety of coping scales used without validation in PD has been cited as a possible cause of this inconsistency. The present study sought to examine the validity of the coping inventory for stressful situations (CISS) in a sample of patients with PD. METHODS: Five hundred and twenty-five patients with PD were recruited as part of a longitudinal investigation of mood states in PD. Four hundred and seventy-one participants completed the CISS. Confirmatory factor analysis was used to explore the structural validity of the scale. Internal reliability, test-retest reliability, convergent validity and discriminant validity were assessed using Cronbach's alpha, intraclass correlations and Pearson's correlations. RESULTS: Both three and four factor solutions were examined. The four factor model was found to provide a better fit of the data than the three factor model. The internal reliability, discriminant validity, convergent validity, and test-retest reliability of the CISS scales were shown to be good. Use of emotion-focused coping was associated with greater depression and anxiety whilst, task-oriented coping was associated with better psychological well-being. CONCLUSION: The results provide support for the validity and reliability of the CISS as a measure of coping in patients with PD. Further research into the relationship between coping and well-being is warranted. The identification of helpful and unhelpful coping strategies may guide the development of evidence-based therapies to improve well-being in patients with PD.

Apathy and cortical atrophy in Alzheimer's disease.

OBJECTIVES: Apathy has been reported as the most prevalent behavioural symptom experienced in Alzheimer's disease (AD), associated with greater functional decline and caregiver distress. The aim of the current study was to investigate structural correlates of apathy in AD using magnetic resonance imaging (MRI) regional volume and regional cortical thickness measures. METHODS: Semi-structured interviews were conducted with 111 AD patients and their caregivers as part of the European multi-centre study AddNeuroMed. Apathy was measured using the apathy domain of the Neuropsychiatric Inventory (NPI). All AD patients were scanned using a 1.5T MRI scanner and the images analysed using an automated analysis pipeline. RESULTS: We found apathy to be the most prevalent neuropsychiatric symptom occurring in 57% of patients. Apathetic patients had significantly greater cortical thinning in left caudal anterior cingulate cortex (ACC) and left lateral orbitofrontal cortex (OFC), as well as left superior and ventrolateral frontal regions, than those without apathy symptoms. CONCLUSIONS: Apathy is mediated by frontocortical structures but this is specific to the left hemisphere at least for patients in the mild to moderate stages of AD.

Insight, cognition and quality of life in Alzheimer's disease.

BACKGROUND: The detrimental impact of dementia upon patient health-related quality of life (HRQL) is well established, as is the importance of improving HRQL. However, relatively little is known about the natural history of HRQL in dementia and those factors influencing it. This limited knowledge potentially restricts the evaluation of the efficacy of interventions designed to improve HRQL. One such area concerns the relationship between HRQL and patient insight. It remains unclear what impact, if any, impaired insight has upon a patient's HRQL. The present study aimed to investigate the relationship between insight and HRQL in a sample of patients with Alzheimer's disease (AD) and their carers. METHODS: 256 patients with AD were recruited as part of AddNeuroMed, a multicentre European AD biomarkers study. Of these, 174 completed a quality-of-life measure in addition to a comprehensive battery of clinical and neuropsychological assessments. RESULTS: Insight was found to be differentially related to patient perceptions of HRQL in mild and moderate dementia. Within moderate dementia, impaired insight was associated with better perceived HRQL. Conversely, cognition, but not insight, was associated with impaired HRQL in mild dementia. Insight was not found to be associated with carer perceptions of patient HRQL. CONCLUSION: Impairment of insight is associated with better HRQL in moderate dementia. This finding has implications for interventions which focus on increasing patient awareness and orientation, as impairment of insight appears to have a positive impact upon HRQL.

Outcome of Weekly Carboplatin-Paclitaxel-based Definitive Chemoradiation in Oesophageal Cancer in Patients Not Considered to be Suitable for Platinum-Fluoropyrimidine-based Treatment: A Multicentre, Retrospective Review.

AIMS: Although cisplatin-fluoropyrimidine-based definitive chemoradiotherapy (dCRT) is a standard of care for oesophageal cancer, toxicity is significant and limits its use in elderly and frail patients. Weekly carboplatin-paclitaxel-based dCRT provides a viable alternative, although prospective data are lacking in the dCRT setting. Here we report the results of a national, multicentre retrospective review of outcome in patients treated with weekly carboplatin-paclitaxel-based dCRT. MATERIALS AND METHODS: In this multicentre retrospective study of nine radiotherapy centres across the UK we evaluated the outcome of patients who had non-metastatic, histologically confirmed carcinoma of the oesophagus (adenocarcinoma, squamous cell or undifferentiated; World Health Organization performance status 0-2; stage I-III disease) and had been selected to receive weekly carboplatin-paclitaxel-based dCRT as they were considered not suitable for cisplatin-fluoropyrimidine-based dCRT. dCRT consisted of carboplatin AUC 2 and paclitaxel 50 mg/m2 (days 1, 8, 15, 22, 29) and the recommended radiation dose was 50 Gy in 25 daily fractions. We assessed overall survival, progression-free survival (PFS; overall, local and distant), proportion of patients who were failure free at the response assessment (12 weeks after dCRT), treatment compliance and toxicity. RESULTS: In total, 214 patients from nine UK centres were treated between 15 February 2013 and 19 March 2019: 39.7% of patients were ≥75 years; 18.7% ≥ 80 years. Indications for weekly carboplatin-paclitaxel-based dCRT were comorbidities (47.2%), clinician choice (36.4%) and poor tolerance/progression on cisplatin-fluoropyrimidine induction chemotherapy (15.8%). The median overall survival was 24.28 months (95% confidence interval 20.07-30.09) and the median PFS was 16.33 months (95% confidence interval 14.29-20.96). Following treatment, 69.1% (96/139) had a combined complete response on endoscopy with non-progression (complete response/partial response/stable disease) on imaging. The 1- and 2-year overall survival rates for this patient group were 81.9% (95% confidence interval 75.6-86.8%) and 50.6% (95% confidence interval 40.5-60.0%), respectively. Thirty-three per cent (n = 70) of patients experienced at least one grade 3 + acute toxicity (grade 3/4 haematological: 10%; grade 3/4 non-haematological: 32%) and there were no treatment-related deaths. 86.9% of patients completed at least four cycles of concomitant weekly carboplatin-paclitaxel-based chemotherapy and planned radiotherapy was completed in 97.7% (209/214). CONCLUSION: Weekly carboplatin-paclitaxel-based CRT seems to be well tolerated in elderly patients and in those with comorbidities, where cisplatin-fluoropyrimidine-based dCRT is contraindicated. Survival outcomes are comparable with cisplatin-fluoropyrimidine-based dCRT.

Stomach Dose-Volume Predicts Acute Gastrointestinal Toxicity in Chemoradiotherapy for Locally Advanced Pancreatic Cancer.

AIMS: Gastrointestinal toxicity impedes dose escalation in chemoradiotherapy for hepatobiliary malignancies. Toxicity risk depends on clinical and radiotherapy metrics. We aimed to identify predictive factors using data from two prospective phase II clinical trials of locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Ninety-one patients with available data from the ARCII (59.4 Gy in 33 fractions with gemcitabine, cisplatin and nelfinavir, n = 23) and SCALOP (50.4 Gy in 28 fractions with capecitabine or gemcitabine, n = 74) trials were studied. The independent variables analysed comprised age, sex, performance status, baseline symptoms, tumour size, weight loss, chemotherapy regimen and dose-volume histogram of stomach and duodenum in 5 Gy bins. The outcome measures used were Common Terminology Criteria of Adverse Events (CTCAE) grade and risk of CTCAE grade ≥2 acute upper gastrointestinal toxicity (anorexia, pain, nausea and/or vomiting). The risk of CTCAE grade ≥2 events was modelled using multivariable logistic regression and prediction of severity grade using ordinal regression. RESULTS: CTCAE grade ≥2 symptoms occurred in 38 patients (42%). On univariate analysis, stomach V35-45Gy was predictive of risk (odds ratio 1.035, 95% confidence interval 1.007-1.063) and grade (1.023, 1.003-1.044) of toxicity. The area under the curve was 0.632 (0.516-0.747) with toxicity risk 33/66 (50%) above and 5/25 (20%) below the optimal discriminatory threshold (7.1 cm3). Using a threshold of 30 cm3, risk was 13/20 (65%) versus 25/71 (35%). The optimal multivariable logistic regression model incorporated patient sex, chemotherapy regimen and stomach V35-45Gy. Receiving gemcitabine rather than capecitabine (odds ratio 3.965, 95% confidence interval 1.274-12.342) and weight loss during induction chemotherapy (1.216, 1.043-1.419) were significant predictors for the SCALOP cohort, whereas age predicted toxicity risk in ARCII only (1.344, 1.015-1.780). Duodenum dose-volume did not predict toxicity risk or severity in any cohort. CONCLUSIONS: In chemoradiotherapy for LAPC the volume of stomach irradiated to a moderately high dose (35-45 Gy) predicts the incidence and severity of acute toxicity. Other predictive factors can include age, sex, recent weight loss and concomitant chemotherapy agents.

Distant delivery of a mindfulness-based intervention for people with Parkinson's disease: the study protocol of a randomised pilot trial.

BACKGROUND: Psychological difficulties, especially depression and anxiety, are the most prevalent non-motor symptoms in Parkinson's disease. Pharmacological treatments for these conditions appear relatively ineffective in Parkinson's disease. Mindfulness courses are increasingly popular and recognised as effective for managing emotional states, and there is growing evidence for the effectiveness of mindfulness courses for people with long-term medical conditions. With this exploratory pilot trial, we want to assess the feasibility of the procedures and processes, including recruitment, most appropriate outcome measure(s), acceptability of type and number of measures, potential nocebo effects, and potential effectiveness and cost-effectiveness of a specially adapted distance-delivered mindfulness-based intervention in people affected by Parkinson's disease. METHODS/DESIGN: This is a pilot two-arm randomised parallel group controlled trial. Sixty participants who meet eligibility criteria will be randomly assigned either to an 8-week mindfulness-based intervention group or a wait-list control group. The mindfulness intervention will include 1-h weekly sessions delivered by a health psychologist trained to facilitate mindfulness courses. Participants in both groups will complete standardised questionnaires assessing anxiety, depression, pain, insomnia, fatigue, and daily activities at four time points (baseline, 4, 8, and 20 weeks). The analysis will also consider potential mechanisms of change, such as acceptance, self-compassion, and tolerance of uncertainty, as well as health economic outcomes. Participants' experiences of the mindfulness interventions will be explored via in-depth interviews. DISCUSSION: A mindfulness-based intervention for people with Parkinson's delivered remotely, through Skype group videoconferences, may represent a viable, more accessible, intervention for people with mobility limitations and people who live in rural areas. The trial will provide important information about the feasibility, potential efficacy and cost-effectiveness, and acceptability of the intervention as well as mechanisms of psychosocial adjustment. The results of this pilot trial will help us design a phase III trial to assess efficacy of an online mindfulness-based intervention in Parkinson's disease and evaluate significance. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02683330.

Premating, not postmating, barriers drive genetic dynamics in experimental hybrid populations of the endangered Sonoran topminnow.

The timing and pattern of reproductive barrier formation in allopatric populations has received much less attention than the accumulation of reproductive barriers in sympatry. The theory of allopatric speciation suggests that reproductive barriers evolve simply as by-products of overall genetic divergence. However, observations of enhanced premating barriers in allopatric populations suggest that sexual selection driven by intraspecific competition for mates may enhance species-specific signals and accelerate the speciation process. In a previous series of laboratory trials, we examined the strength of premating and postmating barriers in an allopatric species pair of the endangered Sonoran topminnow, Poeciliopsis occidentalis and P. sonoriensis. Behavioral observations provided evidence of asymmetrical assortative mating, while reduced brood sizes and male-biased F(1) sex ratios suggest postmating incompatibilities. Here we examine the combined effects of premating and postmating barriers on the genetic makeup of mixed populations, using cytonuclear genotype frequencies of first- and second-generation offspring. Observed genotype frequencies strongly reflect the directional assortative mating observed in behavioral trials, illustrating how isolating barriers that act earlier in the reproductive cycle will have a greater effect on total reproductive isolation and may be more important to speciation than subsequent postmating reproductive barriers.

Management of spotted wilt vectored by Frankliniella fusca (Thysanoptera: Thripidae) in Virginia market-type peanut.

Field tests were conducted during 2001 and 2002 in northeastern North Carolina to evaluate the impact of cultural practices and in-furrow insecticides on the incidence of Tomato spotted wilt virus (genus Tospovirus, family Bunyaviridae, TSWV), which is transmitted to peanut, Arachis hypogaea L., primarily by tobacco thrips, Frankliniella fusca Hinds (Thysanoptera: Thripidae). Treatments included in row plant populations of 7, 13, and 17 plants per meter; the virginia market-type 'NC V-11' and 'Perry'; planting dates of early and late May; and phorate and aldicarb insecticide applied in-furrow. The incidence of plants expressing visual symptoms of spotted wilt was recorded from mid-June through mid-September. Treatment factors that reduced the incidence of symptoms of plants expressing spotted wilt symptoms included establishing higher plant densities, delaying planting from early May until late May, and applying the in-furrow insecticide phorate. Peanut cultivar did not have a consistent, significant effect on the incidence of symptomatic plants in this experiment.

Endogenous adenosine, A1 adenosine receptor, and pertussis toxin sensitive guanine nucleotide binding protein mediate hypoxia induced AV nodal conduction block in guinea pig heart in vivo.

OBJECTIVE: The aim was to study the mechanism of global hypoxia induced atrioventricular (AV) nodal conduction block in vivo using a guinea pig model. METHODS: Animals subjected to 10 min periods of global hypoxia, induced by decremental changes in O2 content in the inhaled gas mixture, were randomly divided into three groups: group I = control; group II = animals treated with a new selective A1 adenosine receptor antagonist, N0861 (N6-endo-norbornan-2-yl-9-methyladenine); and group III-animals treated with pertussis toxin, an irreversible inhibitor of specific guanine nucleotide binding proteins (G protein). RESULTS: Progressive incremental hypoxia was associated with progressive AV nodal conduction delay culminating in a complete block. In addition, there was an inverse relationship between the severity of hypoxia and time to AV nodal block. Both N0861 and pertussis toxin treatment significantly reduced the degree of hypoxia induced AV nodal conduction block and delayed its appearance. CONCLUSIONS: (1) Endogenous adenosine released during acute global hypoxia causes AV nodal conduction block observed under these conditions in the guinea pig heart in vivo; and (2) this action of adenosine in the AV node is mediated by an A1 adenosine receptor and a pertussis toxin sensitive G protein.