An Overview of the Role of Radiotherapy in the Treatment of Small Cell Lung Cancer - A Mainstay of Treatment or a Modality in Decline?

AIMS: Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. Chemotherapy, immunotherapy and radiotherapy all play important roles in the management of SCLC. The aim of this study was to provide a comprehensive overview of the role and evidence of radiotherapy in the cure and palliation of SCLC. MATERIALS AND METHODS: The search strategy included a search of the PubMed database, hand searches, reference lists of relevant review articles and relevant published abstracts. CLINICALTRIALS: gov was also queried for relevant trials. RESULTS: Thoracic radiotherapy improves overall survival in limited stage SCLC, but the timing and dose remain controversial. The role of thoracic radiotherapy in extensive stage SCLC with immunotherapy is the subject of several ongoing trials. Current evidence supports the use of prophylactic cranial irradiation (PCI) for limited stage SCLC but the evidence is equivocal in extensive stage SCLC. Whole brain radiotherapy is well established for the treatment of brain metastases but evidence is rapidly accumulating for the use of stereotactic radiosurgery. Further studies will define the role of PCI, whole brain radiotherapy and hippocampal avoidant PCI in the immunotherapy era. CONCLUSION: Radiotherapy is an essential component in the multimodality management of SCLC. Technological advances have allowed safer delivery of radiotherapy with reduced toxicities. Discussion at multidisciplinary team meetings is important to ensure radiotherapy is considered and offered in appropriate patients.

A novel missense mutation in NR0B1 causes delayed-onset primary adrenal insufficiency in adults.

A novel missense mutation (c.775T>C; p.ser259Pro) in the NROBI gene cause a late-onset adrenal insufficiency without hypogonadism.

[Psychosocial Aspects in Cardiac Rehabilitation: From Theory to Practice. A Position Paper From the Cardiac Rehabilitation Section of The European Association of Cardiovascular Prevention and Rehabilitation of the European Society of Cardiology].

A large body of empirical research shows that psychosocial risk factors (PSRFs) such as low socio-economic status, social isolation, stress, type-D personality, depression and anxiety increase the risk of incident coronary heart disease (CHD) and also contribute to poorer health-related quality of life (HRQoL) and prognosis in patients with establishedCHD. PSRFs may also act as barriers to lifestyle changes and treatment adherence and may moderate the effects of cardiac rehabilitation (CR). Furthermore, there appears to be a bidirectional interaction between PSRFs and the cardiovascular system. Stress, anxiety and depression affect the cardiovascular system through immune, neuroendocrine and behavioural pathways. In turn, CHD and its associated treatments may lead to distress in patients, including anxiety and depression. In clinical practice, PSRFs can be assessed with single-item screening questions, standardised questionnaires, or structured clinical interviews. Psychotherapy and medication can be considered to alleviate any PSRF-related symptoms and to enhance HRQoL, but the evidence for a definite beneficial effect on cardiac endpoints is inconclusive. A multimodal behavioural intervention, integrating counselling for PSRFs and coping with illness should be included within comprehensive CR. Patients with clinically significant symptoms of distress should be referred for psychological counselling or psychologically focused interventions and/or psychopharmacological treatment. To conclude, the success of CR may critically depend on the interdependence of the body and mind and this interaction needs to be reflected through the assessment and management of PSRFs in line with robust scientific evidence, by trained staff, integrated within the core CR team.

WDR19: an ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigmentosa and in Senior-Loken syndrome.

Autosomal recessive retinitis pigmentosa (arRP) is a clinically and genetically heterogeneous retinal disease that causes blindness. Our purpose was to identify the causal gene, describe the phenotype and delineate the mutation spectrum in a consanguineous Quebec arRP family. We performed Arrayed Primer Extension (APEX) technology to exclude ∼500 arRP mutations in ∼20 genes. Homozygosity mapping [single nucleotide polymorphism (SNP) genotyping] identified 10 novel significant homozygous regions. We performed next generation sequencing and whole exome capture. Sanger sequencing provided cosegregation. We screened another 150 retinitis pigmentosa (RP) and 200 patients with Senior-Løken Syndrome (SLS). We identified a novel missense mutation in WDR19, c.2129T>C which lead to a p.Leu710Ser. We found the same mutation in a second Quebec arRP family. Interestingly, two of seven affected members of the original family developed 'sub-clinical' renal cysts. We hypothesized that more severe WDR19 mutations may lead to severe ciliopathies and found seven WDR19 mutations in five SLS families. We identified a new gene for both arRP and SLS. WDR19 is a ciliary protein associated with the intraflagellar transport machinery. We are currently investigating the full extent of the mutation spectrum. Our findings are crucial in expanding the understanding of childhood blindness and identifying new genes.

The small-nucleolar RNAs commonly used for microRNA normalisation correlate with tumour pathology and prognosis.

BACKGROUND: To investigate small-nucleolar RNAs (snoRNAs) as reference genes when measuring miRNA expression in tumour samples, given emerging evidence for their role in cancer. METHODS: Four snoRNAs, commonly used for normalisation, RNU44, RNU48, RNU43 and RNU6B, and miRNA known to be associated with pathological factors, were measured by real-time polymerase chain reaction in two patient series: 219 breast cancer and 46 head and neck squamous cell carcinoma (HNSCC). SnoRNA and miRNA were then correlated with clinicopathological features and prognosis. RESULTS: Small-nucleolar RNA expression was as variable as miRNA expression (miR-21, miR-210, miR-10b). Normalising miRNA PCR expression data to these recommended snoRNAs introduced bias in associations between miRNA and pathology or outcome. Low snoRNA expression correlated with markers of aggressive pathology. Low levels of RNU44 were associated with a poor prognosis. RNU44 is an intronic gene in a cluster of highly conserved snoRNAs in the growth arrest specific 5 (GAS5) transcript, which is normally upregulated to arrest cell growth under stress. Low-tumour GAS5 expression was associated with a poor prognosis. RNU48 and RNU43 were also identified as intronic snoRNAs within genes that are dysregulated in cancer. CONCLUSION: Small-nucleolar RNAs are important in cancer prognosis, and their use as reference genes can introduce bias when determining miRNA expression.

Symptom management for irritable bowel syndrome: a pilot randomized controlled trial of acupuncture/moxibustion.

The purpose of this pilot study was to assess the effect of an individualized traditional Chinese medicine (TCM) acupuncture and moxibustion (Acu/Moxa) treatment on symptom control in patients with irritable bowel syndrome (IBS) in a preliminary, randomized, sham/placebo-controlled trial. Twenty-nine men and women with IBS were randomized to either individualized Acu/Moxa (treatment group) or sham/placebo Acu/Moxa (control group). All subjects were assessed by a diagnostic acupuncturist for a TCM evaluation and individualized point prescription. Only those subjects assigned to the experimental group received the individually prescribed treatment. The diagnostic acupuncturist did not administer treatments and was blind to treatment assignments. All subjects kept a symptom diary for the duration of the study, enabling measurement of symptom frequency, severity, and improvement. The Clinical Global Impression Scale was administered preintervention to establish baseline severity and on completion of the 4-week, eight-session treatment intervention. After 4 weeks of twice-weekly Acu/Moxa treatment, average daily abdominal pain/discomfort improved whereas the control group showed minimal reduction. This between-group difference adjusted for baseline difference was statistically significant. The intestinal gas, bloating, and stool consistency composite score showed a similar pattern of improvement. The findings indicate that Acu/Moxa treatment shows promise in the area of symptom management for IBS.

Understanding diagnostic reasoning in TCM practice: tongue diagnosis.

BACKGROUND: Traditional Chinese medicine (TCM) diagnosis is a complex multifaceted process that often yields multiple differential diagnoses and subdiagnoses. OBJECTIVES: The aims of this study were to (1) understand cognitive strategies and diagnostic reasoning processes of TCM practitioners engaged in tongue diagnosis and (2) investigate TCM practitioners' diagnostic accuracy. Clinical decision making and problem solving frameworks served as a basis for this study. METHODS: Nine TCM practitioners verbalized their thinking processes via think-aloud protocols and were audiotaped while engaged in the cognitive task of tongue diagnosis. Protocol analysis was used to identify TCM diagnostic reasoning patterns. Diagnostic accuracy was assessed by participant self-report and via independent TCM expert judges. RESULTS: Protocol analysis revealed that TCM practitioners use systematic processes to arrive at diagnoses and that there were differences between novices and experts in both pre- and post-adjustments after viewing case histories. Novices tended to use more descriptors and come to the diagnoses earlier. Experts tended to use higher-level intellectual processes when coming to their diagnoses and tended to use these terms earlier in the process. Correlations between practitioner self-assessment and judges' ratings of diagnostic accuracy were noted and corollary case history information improved diagnostic accuracies. CONCLUSION: TCM practitioners use systematic reasoning patterns to determine diagnoses associated with evaluation of tongues. These processes are congruent with those observed in Western medicine whereby clinician reasoning involves a combination of analytical reasoning of domain knowledge and the use of exemplar patterns. An explicit understanding of TCM reasoning processes can inform clinical practice and education and will facilitate the development of supporting technologies and identification of best practices.

Clinical trial recruitment and retention of a vulnerable population: HIV patients with chronic diarrhea.

This article describes the recruitment and retention strategies implemented for a prospective, randomized, clinical trial conducted at a single study facility. The purpose of the study was to examine the effects of a nutritional intervention to reduce the episodes of diarrhea in patients with the human immunodeficiency virus/acquired immune deficiency syndrome. This article reviews the challenges faced by the research team during the conduct of the study and discusses the approaches implemented to reduce the barriers to study participation.

A comparison of foetal and labour outcomes in Caucasian and Afro-Caribbean women with diabetes in pregnancy.

Materno-foetal complications have an increased prevalence in pregnancies complicated by diabetes. Ethnicity and cultural background may further affect these outcomes. In this study, we compared labour and foetal outcomes in Afro-Caribbean and Caucasian women with diabetes in pregnancy, using the Birmingham computerised database of diabetes in pregnancy. A retrospective analysis, covering the period 1990-2002, was employed. Foetal outcomes included early foetal loss, neonatal and perinatal mortality, congenital malformations and infant size at delivery. Labour outcomes assessed were mode and time of delivery. Overall, Afro-Caribbean women achieve similar results to Caucasian women. No significant differences were seen in foetal outcomes between the two cohorts or between diabetic subtypes. Afro-Caribbean women were more likely to have a vaginal delivery, but present later for their first antenatal visit compared with Caucasian women. Variations in culture or access to health care may account for these differences. An awareness of the specific needs of ethnic minorities is essential to ensure that this encouraging trend continues.

Redesigning postnatal care: a randomised controlled trial of protocol-based midwifery-led care focused on individual women's physical and psychological health needs.

OBJECTIVES: To develop, implement and test the cost-effectiveness of redesigned postnatal care compared with current care on women's physical and psychological health. DESIGN: A cluster randomised controlled trial, with general practice as the unit of randomisation. Recruited women were followed up by postal questionnaire at 4 and 12 months postpartum and further data collected from midwife and general practice sources. SETTING: Thirty-six randomly selected general practice clusters in the West Midlands Health Region, UK. PARTICIPANTS: All women expected to be resident within recruited practices for postnatal care were eligible for inclusion. Attached midwives recruited 1087 women in the intervention and 977 in the control practice clusters. INTERVENTIONS: The systematic identification and management of women's health problems, led by midwives with general practitioner contact only when required. Symptom checklists and the Edinburgh Postnatal Depression Scale (EPDS) were used at various times to maximise the identification of problems, and individual care and visit plans based on needs. Evidence-based guidelines were used to manage needs. Care was delivered over a longer period. MAIN OUTCOME MEASURES: Women's health at 4 and 12 months, assessed by the Physical and Mental Component Scores (PCS and MCS) of the Short-Form 36 (SF-36) and the EPDS. Women's views about care, reported morbidity at 12 months, health service usage during the year, 'good practice' indicators and health professionals' views about care were secondary outcomes. RESULTS: At 4 and 12 months postpartum the mean MCS and EPDS scores were significantly better in the intervention group and the proportion of women with an EPDS score of 13+ (indicative of probable depression) was significantly lower relative to controls. The physical health score (PCS) did not differ. Health service usage was significantly less in the intervention group as well as reported psychological morbidity at 12 months. Women's views about care were either more positive or did not differ. Intervention midwives were more satisfied with redesigned care than control midwives were with standard care. Intervention care was cost-effective since outcomes were better and costs did not differ substantially. CONCLUSIONS: The redesigned community postnatal care led by midwives and delivered over a longer period, resulted in an improvement in women's mental health at 4 months postpartum, which persisted at 12 months and at equivalent overall cost. It is suggested that further research should focus on: the identification of postnatal depression through screening; whether fewer adverse longer term effects might be demonstrated among the children of the women who had the intervention care relative to the controls; testing interventions to reduce physical morbidity, including studies to validate measures of physical health in postpartum women. Further research is also required to investigate appropriate postnatal care for ethnic minority groups.

Quality of brief guidelines produced by professional bodies: a study of the 'green-top' guidelines by the UK Royal College of Obstetricians and Gynaecologists.

Clinicians ignore lengthy guidelines and prefer pocket cards and concise pamphlets. However, brevity in guidelines may lead to deficiency in quality. Our objective, therefore, was to examine the quality of brief guidelines produced by professional bodies, using those produced by the UK Royal College of Obstetricians and Gynaecologists (RCOG) as an example. We assessed all 22 'green-top' guidelines, produced by September 2002, for quality using a validated 37-item appraisal instrument. This instrument evaluated the guidelines on three dimensions, namely rigour of development, context and content and applicability. Ten (45%), 18 (82%) and five (23%) of the 22 guidelines met at least half the quality criteria for rigour of development, context and content and applicability, respectively. We conclude that the brief guidelines were deficient in several specific quality items, particularly those in the applicability dimension. Guideline developers need to achieve the higher quality standards expected of professional bodies.

Pregnancy in women with Type 2 diabetes: 12 years outcome data 1990-2002.

AIM: Twelve years' outcome analysis of pregnancies in women with Type 2 diabetes in a multiethnic geographically defined area. METHODS: Information about 182 women delivered between 1990 and 2002 was ascertained from a regional computerized database. The main outcome measures were rates of miscarriage, stillbirth, neonatal/postnatal deaths, congenital malformations, birth weight, mode of delivery, and neonatal unit care as well as maternal morbidities of polyhydramnios, postpartum haemorrhage, pregnancy-induced hypertension/pre-eclampsia. RESULTS: Among 182 singleton pregnancies, 161 (88%) resulted in a live outcome. There were 16 (8.8%) spontaneous miscarriages, two (1.2%) stillbirths, and three (1.6%) terminations. Congenital malformations occurred in 18 pregnancies (99/1000). There were two early and one late neonatal deaths and two further deaths in the postnatal period. Twenty-eight percent of infants were large for gestational age, with 15 (9.3%) greater than 4 kg. Fifty-three percent were delivered by caesarean section and 68 (37%) required admission to neonatal unit (NNU) care. Hypertension/pre-eclampsia was two times, polyhydramnios three times, and postpartum haemorrhage six times more common than in non-diabetic women. CONCLUSIONS: Women with Type 2 diabetes have a less satisfactory pregnancy outcome compared with the general population. Infants have a two-fold greater risk of stillbirth, a 2.5-fold greater risk of a perinatal mortality, a 3.5-fold greater risk of death within the first month and a six-fold greater risk of death up to 1 year compared with regional/national figures. They have an 11 times greater risk of a congenital malformation. We need to develop better educational and screening strategies if we are to improve.

From minimal background diabetic retinopathy to profuse sight threatening vitreoretinal haemorrhage: management issues in a case of pregestational diabetes and pregnancy.

Deterioration of retinopathy is a recognized complication of pregnancy in Type 1 diabetes. We discuss management issues relating to a case of rapid sight-threatening progression of retinopathy in pregnancy complicated by pregestational diabetes.

Effects of redesigned community postnatal care on womens' health 4 months after birth: a cluster randomised controlled trial.

BACKGROUND: Much postpartum physical and psychological morbidity is not addressed by present care, which tends to focus on routine examinations. We undertook a cluster randomised controlled trial to assess community postnatal care that has been redesigned to identify and manage individual needs. METHODS: We randomly allocated 36 general practice clusters from the West Midlands health region of the UK to intervention (n=17) or control (19) care. Midwives from the practices recruited women and provided care. 1087 (53%) of 2064 women were in practices randomly assigned to the intervention group, with 977 (47%) women in practices assigned to the control group. Care was led by midwives, with no routine contact with general practitioners, and was extended to 3 months. Midwives used symptom checklists and the Edinburgh postnatal depression scale (EPDS) to identify health needs and guidelines for the management of these needs. Primary outcomes at 4 months were obtained by postal questionnaire and included the women's short form 36 physical (PCS) and mental (MCS) component summary scores and the EPDS. Secondary outcomes were women's views about care. Multilevel analysis accounted for possible cluster effects. FINDINGS: 801 (77%) of 1087 women in the intervention group and 702 (76%) of 977 controls responded at 4 months. Women's mental health measures were significantly better in the intervention group (MCS, 3.03 [95% CI 1.53-4.52]; EPDS -1.92 [-2.55 to -1.29]; EPDS 13+ odds ratio 0.57 [0.43-0.76]) than in controls, but the physical health score did not differ. INTERPRETATION: Redesign of care so that it is midwife-led, flexible, and tailored to needs, could help to improve women's mental health and reduce probable depression at 4 months' postpartum.

Critical appraisal in clinical practice: sometimes irrelevant, occasionally invalid.

A core activity of evidence-based practice is the search for and appraisal of evidence on specific clinical issues. Clinicians vary in their competence in this process; we therefore developed a 16-item checklist for quality of content (relevance and validity) and presentation (useability, attribution, currency and contact details). This was applied to a set of 55 consecutive appraisals conducted by clinicians and posted at a web-based medical journal club site. Questions were well formulated in 51/55 (92%) of the appraisals. However, 22% of appraisals missed the most relevant articles to answer the clinical question. Validity of articles was well appraised, with methodological information and data accurately extracted in 84% and accurate conversion to clinically meaningful summary statistics in 87%. The appraisals were presented in a useable way with appropriate and clear bottom-lines stated in 95%. The weakest link in production of good-quality critical appraisals was identification of relevant articles. This should be a focus for evidence-based medicine and critical appraisal skills.

Aspirin for the prevention of preeclampsia in women with abnormal uterine artery Doppler: a meta-analysis.

OBJECTIVE: To determine the effectiveness of aspirin to prevent preeclampsia in women identified as high risk for preeclampsia by an abnormal second-trimester uterine artery Doppler examination. DATA SOURCES: Searches were conducted in MEDLINE, Embase, the Cochrane Controlled Trials Register, and Science Citation Index for randomized trials published from 1966 to 2000, using the following medical subject headings and key words: "aspirin," "antiplatelet*," "salicyl*," "acetylsalicyl*," "platelet aggregation inhibitors," "ultrasonography," "ultraso*," and "Doppler." STUDY SELECTION: We included all randomized trials that evaluated the effectiveness of aspirin compared with placebo or no treatment in women with an abnormal uterine artery Doppler and that reported clinically relevant perinatal and maternal outcomes. Study selection, quality assessment, and data extraction were performed in duplicate. TABULATION, INTEGRATION, AND RESULTS: There were five relevant trials. Pooling of results from these trials showed a significant benefit of aspirin in reducing preeclampsia (odds ratio [OR] 0.55, 95% confidence interval [CI] 0.32, 0.95). The baseline risk of preeclampsia in women with abnormal uterine artery Doppler was 16%, and the number of women needed to be treated with aspirin to prevent one case of preeclampsia was 16 (95% CI 8, 316). Women on aspirin had babies who were on average 82 g heavier than controls, but this result did not reach statistical significance (weighted mean difference 81.5, 95% CI 40.27, 203.27). CONCLUSION: Uterine artery Doppler assessment identifies high-risk women in whom aspirin therapy results in a significant reduction in preeclampsia.