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PubMed2000

Corticosteroids for pulmonary sarcoidosis.

BACKGROUND: Pulmonary sarcoidosis is a common condition with an unpredictable course. Oral or inhaled steroids are widely used in its treatment, but there is no consensus about when and in whom therapy should be initiated, what dose should be given and for how long. Corticosteroids given for several months have deleterious side-effects so it is important to know whether they have any maintained benefit in pulmonary sarcoidosis. OBJECTIVES: To determine the randomised controlled trial (RCT) evidence for the benefit of corticosteroids (oral or inhaled) in the treatment of pulmonary sarcoidosis. SEARCH STRATEGY: The Cochrane Airways Group interstitial lung disease RCT register was searched using the terms: sarcoidosis and (steroid* OR corticosteroid* OR prednisolone OR prednisone OR beclomethasone OR budesonide OR fluticasone). Bibliographies of retrieved RCTs and reviews were searched for additional RCTs. Pharmaceutical companies and authors of identified RCTs were contacted for other published and unpublished studies. SELECTION CRITERIA: Two reviewers independently assessed full text articles for inclusion based upon the following criteria: the study had to be a RCT or controlled clinical trial in adults with histological evidence of pulmonary sarcoidosis. DATA COLLECTION AND ANALYSIS: Study quality was assessed and data extracted independently by two reviewers. Outcomes were analysed as continuous and dichotomous outcomes, using standard statistical techniques. MAIN RESULTS: Eight RCTs were identified, two had insufficient data for any analysis. There were 338 patients in the four usable trials of oral steroids, and 66 patients in two trials of inhaled steroids. The oral steroid dose was equivalent to prednisolone 15-40 mg/day. The inhaled steroid was budesonide 0.8 - 1.2 mg/day. Outcomes were symptoms, chest X-ray (CXR) changes, lung function and global scores (a combination of all three outcomes). Oral steroids improved the CXR over 6-24 months. One study showed no improvement in lung function, in another there was an improvement in diffusing capacity in the treated group. Global scores improved in patients with stage 2 and 3 disease but not with stage 1 disease. There were no data on side-effects. Inhaled steroids had no effect on CXR. In one study diffusing capacity improved. In another, symptoms improved at the end of six months of treatment. REVIEWER'S CONCLUSIONS: Oral steroids improved the chest X-ray and a global score of CXR, symptoms and spirometry over 6-24 months. There is little evidence of an improvement in lung function. There are no data beyond 2 years to indicate whether oral steroids have any modifying effect on long-term disease progression. Oral steroids are indicated for patients with Stage 2 and 3 disease with moderate - severe or progressive symptoms or CXR changes. The available data provide no guidance for the management of this disease after 2 years. Short term (less than six months) of inhaled steroids may improved symptoms, perhaps in patients who mainly have cough.

Administration, Inhalation↗

PubMed2005

Art therapy for schizophrenia or schizophrenia-like illnesses.

BACKGROUND: Many people with schizophrenia or schizophrenia-like illnesses continue to experience symptoms in spite of medication. In addition to medication, creative therapies, such as art therapy, may be helpful. Art therapy allows exploration of the patient's inner world in a non-threatening way through a therapeutic relationship and the use of art materials. It was mainly developed in adult psychiatric inpatient units and was designed for use with people for whom verbal psychotherapy would be impossible. OBJECTIVES: To review the effects of art therapy as an adjunctive treatment for schizophrenia compared with standard care and other psychosocial interventions. SEARCH STRATEGY: We updated the search of the Cochrane Schizophrenia Group's Register (February 2005), hand searched reference lists and 'Inscape' (the Journal of the British Association of Art Therapists), and contacted relevant authors. SELECTION CRITERIA: We included all randomised controlled trials that compared art therapy with standard care or other psychosocial interventions for schizophrenia. DATA COLLECTION AND ANALYSIS: We reliably selected, quality assessed and extracted data from the studies. We excluded data where more than 50% of participants in any group were lost to follow up. For continuous outcomes we calculated a weighted mean difference and its 95% confidence interval. For binary outcomes we calculated a fixed effects risk ratio (RR), its 95% confidence interval (CI) and a number needed to treat (NNT). MAIN RESULTS: The search identified 61 reports but only two studies (total n=137) met the inclusion criteria. Both compared art therapy plus standard care with standard care alone. More people completed the therapy if allocated to the art therapy group compared with standard care in the short (n=90, 1 RCT, RR 0.97 CI 0.41 to 2.29), medium (n=47, 1 RCT, RR 0.34 CI 0.15 to 0.80) and long term (n=47, 1 RCT, RR 0.96 CI 0.57 to 1.60). Data from one mental state measure (SANS) showed a small but significant difference favouring the art-therapy group (n=73, 1 RCT, WMD -2.3 CI -4.10 to -0.5). In the short term, a measure of social functioning (SFS) showed no clear difference between groups in endpoint scores (n=70, 1 RCT, WMD 7.20 CI -2.53 to 16.93) and quality of life, as measured by the PerQoL, did not indicate effects of art therapy (n=74, 1 RCT, WMD 0.1 CI -2.7 to 0.47). AUTHORS' CONCLUSIONS: Randomised studies are possible in this field. Further evaluation of the use of art therapy for serious mental illnesses is needed as its benefits or harms remain unclear.

Art Therapy↗

PubMed2006

Interventions for the prevention and management of oropharyngeal candidiasis associated with HIV infection in adults and children.

BACKGROUND: Oral candidiasis (OC) associated with human immunodeficiency virus (HIV) infection occurs commonly and recurs frequently, often presenting as an initial manifestation of the disease. Left untreated these lesions contribute considerably to the morbidity associated with HIV infection. Interventions aimed at preventing and treating HIV-associated oral candidal lesions form an integral component of maintaining the quality of life for affected individuals. OBJECTIVES: To determine the effects of any intervention in preventing or treating OC in children and adults with HIV infection. SEARCH STRATEGY: The search strategy was based on that of the HIV/AIDS Cochrane Review Group. The following electronic databases were searched for randomised controlled trials for the years 1982 to 2005: Medline; AIDSearch; EMBASE and CINAHL. The Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness and the Cochrane Central Register of Controlled Trials (CENTRAL) was also searched through May 2005. The abstracts of relevant conferences, including the International Conferences on AIDS and the Conference on Retroviruses and Opportunistic Infections, as indexed by AIDSLINE, were also reviewed. The strategy was iterative, in that references of included studies were searched for additional references. All languages were included. SELECTION CRITERIA: Randomised controlled trials (RCTs) of palliative, preventative or curative therapy were considered, irrespective of whether the control group received a placebo. Participants were HIV positive adults. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the methodological quality of the trials and extracted data. Study authors were contacted for additional data where necessary. MAIN RESULTS: Four trials were conducted in developing countries with eleven of the trials conducted in the United States of America. Twenty eight trials (n=3225) were included. Nineteen trials investigated treatment and nine trials the prevention of OC. One trial, comparing fluconazole and ketoconazole, investigated the treatment of OC in children. Eighteen of the included studies reported CD4 cell counts. None of the included studies investigated the effects of HAART or any other form of antiretroviral treatment on OC treatment or prevention.TreatmentTreatment was assessed in the majority of trials looking at both clinical and mycological cures. In the majority of comparisons there was only one trial. Compared to nystatin, fluconazole favoured clinical cure in adults(1 RCT; n=167; RR 1.69; 95% CI 1.27 to 2.23). There was no difference with regard to clinical cure between fluconazole compared to ketoconazole (2 RCTs; n=83; RR 1.27; 95% CI 0.97 to 1.66), itraconazole (2 RCTs; n=434; RR 1.05; 95% CI 0.94 to 1.16) or clotrimazole (2 RCTs; n=358; RR 1.14; 95% CI 0.92 to 1.42). When compared with clotrimazole, both fluconazole (2 RCTs; n=358; RR 1.47; 95% CI 1.16 to 1.87) and itraconazole (1 RCT; n=123; RR 2.20; 95% CI 1.43 to3.39) proved to be better for mycological cure. Both gentian violet (1 RCT; n=96; RR 5.28; 95% CI 1.23 to 22.55) and ketoconazole (1 RCT; n=92; RR 5.22; 95% CI 1.21 to 22.53) were superior to nystatin in bringing about clinical cure. PreventionSuccessful prevention was defined as the prevention of a relapse while receiving prophylaxis. Fluconazole was compared with placebo in one trial (5 RCTs; n=599; RR 0.61; 95% CI 0.5 to 0.74) and with no treatment in another (1 RCT; n=65; RR 0.16; 95% CI 0.08 to 0.34). In both instances the prevention of clinical episodes was favoured by fluconazole. Comparing continuous fluconazole treatment with intermittent treatment (1 RCT; n=62; RR 0.37; 95% CI 0.15 to 0.92), prevention is favoured by the continuous treatment. AUTHORS' CONCLUSIONS: Implications for practiceDue to only one study in children it is not possible to make recommendations for treatment or prevention of OC in children. Amongst adults, there were few studies per comparison. Due to insufficient evidence no conclusion could be made about the effectiveness of clotrimazole, nystatin, amphotericin B, itraconazole or ketoconazole with regard to OC prophylaxis. In comparison to placebo, fluconazole is an effective preventative intervention. However, the potential for resistant Candida organisms to develop, as well as the cost of prophylaxis, might impact the feasibility of implementation. No studies were found comparing fluconazole with other interventions. Direction of findings suggests that ketoconazole, fluconazole, itraconazole and clotrimazole improved the treatment outcomes. Implications for researchThere is an urgent need for gentian violet and other less expensive anti-fungal drugs for OC treatment to be evaluated in larger studies. More well designed treatment trials with larger sample size are needed to allow for sufficient power to detect differences in not only clinical, but also mycological response and relapse rates. There is also a strong need for more research to be done on the treatment and prevention of OC in children as it is reported that OC is the most frequent fungal infection in children and adolescents who are HIV positive. More research on the effectiveness of less expensive interventions also needs to be done in resource-poor settings. Currently few trials report outcomes related to quality of life, nutrition, or survival. Future researchers should consider measuring these when planning trials. Development of resistance remains under-studied and more work must be done in this area. It is recommended that trials be more standardised and conform more closely to CONSORT as this will improve research and also clinical practice.

Adult↗

PubMed2004

Amphetamines for schizophrenia.

BACKGROUND: It is estimated that between 10% and 65% of people with schizophrenia use illicit drugs such as amphetamines. This group have an increased rate of hospitalisation, homelessness, unemployment and suicide compared with those with schizophrenia who do not abuse drugs. OBJECTIVES: To evaluate the effects of amphetamines for people with schizophrenia in terms of clinically meaningful outcomes, cognitive functioning and physiological tests. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (February 2002). SELECTION CRITERIA: We included all randomised controlled trials investigating the effects of amphetamines on people with schizophrenia, compared with a placebo intervention. DATA COLLECTION AND ANALYSIS: Working independently, we selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate we calculated risk ratios (RR) and their 95% confidence intervals (CI), with the number needed to treat (NNT). For continuous data we calculated Weighted Mean Differences (WMD). MAIN RESULTS: We included four short studies with a total of 83 participants. Data were few and poorly reported. The results indicated a reduction of negative symptoms for people allocated to amphetamines (n = 16, 1 RCT, WMD -3 CI -5.02 to -0.98). No such effect was found for positive symptom change (n = 16, 1 RCT, WMD 0 CI -4.46 to 4.46). Compared with placebo, amphetamines significantly increased metabolism in the left and right cerebellum (n = 23, 1 RCT, WMD 0.12 CI 0.06 to 0.18; n = 23 1 RCT, WMD 0.12 CI 0.06 to 0.18) and left striatum (n = 23, 1 RCT, WMD 0.14 CI 0.00 to 0.28) and also significantly decreased metabolism in the left dorsolateral prefrontal cortex (n = 23, 1 RCT, WMD -0.09 CI -0.17 to -0.01). REVIEWERS' CONCLUSIONS: Understandably amphetamines are rarely formally evaluated in randomised studies and therefore unpublished work in this area is likely to exist. Addition of more studies may clarify reasons why people with schizophrenia persist in taking these harmful stimulants.

Amphetamine-Related Disorders↗

PubMed2006

Antidepressants for the negative symptoms of schizophrenia.

BACKGROUND: Negative symptoms are common in people with schizophrenia and are often difficult to treat with antipsychotic drugs. Treatment often involves the use of various add-on medications such as antidepressants. OBJECTIVES: To review the effects of the combination of antipsychotic and antidepressant drug treatment for management of negative symptoms in schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's register (January 2004). We also contacted authors of included studies in order to identify further trials. SELECTION CRITERIA: We included all randomised controlled trials comparing antipsychotic and antidepressant combinations with antipsychotics alone for the treatment of prominent negative symptoms in schizophrenia and/or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: Working independently, we selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate we calculated the relative risk RR) and their 95% confidence intervals (CI), with the number needed to treat (NNT). MAIN RESULTS: We included five studies (all short-term, total N=190). We found no significant difference for 'leaving the study early for any reason' between the antipsychotic plus antidepressant combination and the control group (n=90, 3 RCTs, RR 3.0 CI 0.35 to 26.04). Leaving early due to adverse events (n=64, 2 RCTs, RR 5.0 CI 0.26 to 97.0) and leaving the study early due to inefficacy (n=34, 1 RCT, RR 3.0 CI 0.13 to 68.84) also showed no significant difference between the two treatment groups. In terms of clinical response, participants treated with the antipsychotic plus antidepressant medications showed a statistically significant greater improvement (n=30, 1 RCT, WMD -1.0 CI -1.61 to -0.39) and showed a significantly lower severity at endpoint (n=30, 1 RCT, WMD -0.9 CI -1.55 to -0.25) on the Clinical Global Impression Scale than those treated with antipsychotics alone. More people allocated to combination therapy had a clinically significant improvement in negative symptoms compared with those given antipsychotics and placebo (n=60, 2 RCTs, RR 0.56 CI 0.32 to 0.97, NNT 3 CI 3 to 34). Significant differences in favour of the combination therapy were seen in different aspects of negative symptoms: 'affective flattening' (n=30, 1 RCT, WMD -7.0 CI -10.37 to -3.63), 'alogia' (n=26, 1 RCT, WMD -3.00 CI -5.14 to -0.86) and 'avolition' (n=30, 1 RCT, WMD -3.0 CI -5.04 to -0.96). No statistically significant difference was found between treatment groups in regards to the outcome 'at least one adverse event' (n=84, 2 RCTs, RR 1.80 CI 0.66 to 4.90). For movement disorders and other adverse effects, no statistically significant differences were found in any of the studies that provided usable data on these outcomes. There are no data at all on outcomes such as compliance, cost, social and cognitive functioning, relapse, recurrence of negative symptoms, rehospitalisation or quality of life. There are no medium or long term data. AUTHORS' CONCLUSIONS: The combination of antipsychotics and antidepressants may be effective in treating negative symptoms of schizophrenia, but the amount of information is currently too limited to allow any firm conclusions. Large, pragmatic, well-designed and reported long term trials are justified.

Antidepressive Agents↗

PubMed2006

Impact of preoperative radiochemotherapy on postoperative course and survival in patients with locally advanced squamous cell oesophageal carcinoma.

BACKGROUND: The aim of this study was to determine the effect of neoadjuvant radiochemotherapy (RCT) on postoperative complications and survival after surgery for locally advanced oesophageal squamous cell carcinoma. METHODS: Postoperative course and survival were compared in 144 patients who had neoadjuvant RCT and 80 control patients who had surgery alone for locally advanced oesophageal squamous cell carcinoma (radiological stage T3, N0 or N1, M0). RESULTS: The two groups were comparable in terms of American Society of Anesthesiologists grade, age, sex, weight loss, tumour location, presence of lymph node metastasis and surgical approach. Postoperative mortality rates were 6.3 and 9 per cent (P=0.481), with morbidity rates of 40.3 and 41 percent (P=0.887) in the RCT and control group respectively. Complete resection (R0) rates were 74.3 and 48 percent respectively (P<0.001). Significant downstaging was observed in the RCT group (P<0.001), with 16.0 percent of patients having a complete pathological response. Median survival was 29 versus 15 months, and the 5-year survival rate 37 versus 17 percent (P=0.002) in RCT and control groups respectively. CONCLUSION: Neoadjuvant RCT significantly enhanced R0 resection and survival rates in patients with stage T3 oesophageal squamous cell carcinoma, with no increase in postoperative mortality and morbidity rates.

Adult↗

PubMed2002

Cost-effectiveness of staging computed tomography of the chest in patients with T2 soft tissue sarcomas.

BACKGROUND: Published practice guidelines recommend routine chest computed tomography (CT) scanning as part of the staging evaluation for patients with T2 soft tissue sarcomas (STS), although there is no direct evidence to support this practice. The objective of this study was to determine the yield and cost-effectiveness of routine versus selective chest CT scanning for the staging of patients with T2 STS and to identify any subgroups for whom a more selective approach to chest CT scanning could be considered. METHODS: Six hundred consecutive patients with primary, nonthoracic, T2 (> 5 cm) STS underwent both chest X-ray (CXR) and chest CT scanning to evaluate the presence of pulmonary metastatic disease (M1). The authors constructed a decision tree that modeled the outcomes of diagnostic testing for two hypothetical diagnostic strategies: 1) routine chest CT (rCT) or 2) CXR and selective chest CT (sCT). The yield and cost of each strategy were determined; the incremental cost-effectiveness ratio (ICER) was calculated as the cost per additional patient with pulmonary metastases identified by rCT versus sCT. RESULTS: The yield of rCT was higher than that of sCT (M1 disease identified in 19.2% vs. 16.0% of patients, respectively), but rCT was more costly ($1301 vs. $418 per patient, respectively). The ICER of rCT compared with sCT was $27,594 per patient identified with pulmonary metastasis. The expected yields, costs, and ICERs of the diagnostic strategies varied across patient subgroups based on grade, anatomic site, and tumor size. CONCLUSIONS: For patients with T2 STS, rCT was most cost-effective in patients with high-grade lesions or extremity lesions. The findings of this study do not support the routine use of chest CT scanning in all patients with T2 STS.

Adolescent↗

PubMed2026

Extended Use of the Omnipod 5 Automated Insulin Delivery System in Adults With Type 1 Diabetes: 12-Month Extension of a Randomized Controlled Trial.

BACKGROUND: The Omnipod 5 Automated Insulin Delivery (AID) System is safe and effective for individuals managing Type 1 diabetes (T1D). Longer-term studies may provide additional evidence of sustained effectiveness and safety of AID system use in T1D. METHODS: This 12-month extension study was conducted following a multicenter randomized controlled trial (RCT) where participants used either AID (Omnipod 5) or standard therapy (current non-automated pump therapy) for 13 weeks. Participants in France (n = 76) could transition to or continue with AID for an additional 12 months. Glycemic, safety, and psychosocial outcomes during or at the end of the extension phase were compared with baseline or end of RCT, as appropriate. RESULTS: Seventy-five participants enrolled in the extension phase. From RCT baseline to the end of the extension phase, time in range 70-180 mg/dL increased by 17.9% (p < 0.0001) or 4.3 h/day to 62.3%. Time above range > 180 mg/dL and mean sensor glucose decreased by 17.7% and 27.8 mg/dL (both p < 0.0001), respectively. HbA1c decreased from 8.33% to 7.18% (-1.14%; p < 0.0001). Glycemic improvements were maintained for those continuing with AID from the RCT intervention group and for those transitioning to AID from standard therapy. Diabetes Quality of Life-brief and Hypoglycemia Confidence Scale scores were maintained or improved at 6 and 12 months compared to RCT baseline. Adverse events were infrequent (12 per 100 person-years). CONCLUSIONS: Findings support the RCT results, demonstrating safety and sustained improvements in glycemic and psychosocial outcomes with the Omnipod 5 System in adults in France with T1D over 12 months. TRIAL REGISTRATION: ClinicalTrials.gov NCT05409131.

Humans↗

PubMed1986

Tissue-specific markers in flow cytometry of urological cancers. II. Cytokeratin and vimentin in renal-cell tumors.

Nine primary human renal-cell tumors (RCT), one lymph-node metastasis, 4 human xenografts of a RCT in nude mice and a rat RCT line were analyzed by flow cytometry (FCM) using propidium iodide for DNA analysis and antibodies to cytokeratin and vimentin in the indirect immunofluorescence technique for labelling of specific tumor-cell populations. By means of 2-dimensional FCM analysis, vimentin- and cytokeratin-positive (tumor) cells were compared and their DNA content and proliferative fraction analyzed separately from those of cytokeratin-negative stromal and inflammatory cells. In primary human RCT, 2 subpopulations of cells were detected and analyzed separately. Small numbers of tumor cells with an abnormal DNA stemline were also detected. In addition, co-expression of intermediate filament proteins of both the cytokeratin and the vimentin types was detected in the aneuploid cell population. Comparison of 2 model systems of RCT with primary human RCT revealed a similar pattern of tumor-cell subfractions within these tumors. The 2-parameter FCM analysis permits the detection of subpopulations in complex cell suspensions and the quantification of these fractions, as well as analysis of their cellular DNA content.

Animals↗

PubMed1999

Might stopping smoking reduce injury death risks? A meta-analysis of randomized, controlled trials.

BACKGROUND: Smokers have excesses of injuries. Randomized, controlled trials (RCT) could assess whether cigarette smoking (smoking) causes (and smoking cessation (cessation) prevents) those injuries. We analyzed injury, accident, suicide, and homicide deaths as secondary endpoints in RCT that induced cessation. METHODS: RCT were sought via MEDLINE, bibliographies, the CDC Smoking and Health database, and the GLOBALink Tobacco listserver. RCT were included if (1) net (intervention minus control) cessation totaled over 10% of all intervention smokers and (2) injury data were available. Relative risks (RR) were summarized by fixed effects modeling. RESULTS: Three trials were located (the Lung Health Study, MRFIT, and Whitehall RCT). In-trial annual point prevalence cessation averaged 41, 46, and 59% in the intervention group smokers versus 17, 22, and 28% in the respective controls. Intervention (cessation) was associated with pooled injury RR of 0.65 within the trials (95% confidence interval (CI) 0.36-1.19) and 0.68 (95% CI 0.43-1.09) with additional follow-up in the Lung Health and MRFIT populations. CONCLUSIONS: The smoking/injury death association is of borderline statistical significance in currently available RCT data. It modestly supports the significant forensic, cohort, case-control, cross-sectional, challenge-rechallenge, in vitro, and animal data suggesting that smoking may cause injury. Direct tests of the hypothesis could strengthen this inference.

Accidents↗

PubMed2001

Doctors' perceptions of the effects of interventions tested in prospective, randomised, controlled, clinical trials: results of a survey of ICU physicians.

OBJECTIVES: To establish a list of therapeutic interventions considered by intensive care unit (ICU) physicians to have been tested by prospective, randomised, controlled clinical trials (RCTs) in critically ill patients, and to survey the perceptions of the same physicians on the therapeutic effect of these interventions as evaluated by RCT. DESIGN AND SETTING: Self-applied questionnaire in an International Symposium of Intensive Care and Emergency Medicine, Brussels, Belgium. PARTICIPANTS: All 3250 registrants at the symposium. MEASUREMENTS AND RESULTS: There were 527 questionnaires completed, and 446 were suitable for analysis. Respondents were asked to list the therapeutic interventions used in intensive care medicine which they believed have been shown by RCTs to improve survival. Using a 5-point Likert scale, respondents were then asked to rate their assessment of the effectiveness of each intervention they listed and, using a 3-point scale, to select their level of confidence in those assessments. A total of 512 interventions were identified by the respondents as having been tested by RCT. Analysing the 42 interventions quoted more than 12 times, 31 were believed by the respondents to have been shown to have a beneficial effect, and 11 to have a harmful effect. Many of the interventions noted have not in fact been subjected to RCT. CONCLUSIONS: Many interventions that have not been tested by RCT were believed to have been tested; conversely, some interventions actually tested by RCT were not mentioned. Few interventions used in the ICU have actually been shown by RCT to have a positive effect on outcome.

Adult↗

PubMed2006

Cognitive-behaviour therapy for chronic fatigue syndrome: comparison of outcomes within and outside the confines of a randomised controlled trial.

Outcomes for cognitive-behaviour therapy (CBT) in randomised controlled trials (RCTs) have rarely been compared to those in routine clinical practice. Taking the case of CBT for chronic fatigue syndrome (CFS), we evaluated the results of a successful RCT against those of the same treatment given in the same setting as part of routine practice. Fatigue and social adjustment scores were compared for patients who received CBT for CFS as part of a RCT (N=30) and patients who received CBT as part of everyday clinical practice (N=384). The results in the RCT were superior to those in routine clinical practice. Between pre-treatment and 6-month follow-up, the RCT showed a larger reduction in fatigue and greater improvement in social adjustment than those in routine treatment. The changes in fatigue scores were similar for both groups during treatment but were greater in the RCT between post-treatment and follow-up. Potential reasons for the superior results of the RCT include patient selection, therapist factors and the use of a manualised treatment protocol. Practitioners need to pay particular attention to relapse prevention and ensuring adequate follow-up in addition to encouraging patients to continue with cognitive-behavioural strategies once treatment has ended.

Adaptation, Psychological↗

PubMed2006

Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouracil: updated results of a randomized multicentric trial in advanced head-and-neck cancer.

PURPOSE: To prove an expected benefit of concurrent radiochemotherapy (RCT), a two-arm randomized multicentric study was performed. In a subgroup analysis the influence of pretherapeutical hemoglobin level (p-Hb) on survival under locoregional control (SLC) was tested. PATIENTS AND METHODS: The study included primarily untreated Stage III/IV (International Union Against Cancer [UICC]) oropharyngeal and hypopharyngeal carcinomas. Patients were randomized to receive either hyperfractionated (hf) and accelerated (acc) RCT with two cycles 5-fluorouracil (600 mg/m(2)/day) and carboplatin (70 mg/m(2)/day) on Days 1-5 and 29-33 or hf-acc radiotherapy (RT) alone. Total RT dose in both arms was 69.9 Gy in 38 days in concomitant boost technique. RESULTS: After a median follow-up time of 57 months, SLC is significantly better in RCT than in RT (p = 0.01), with median SLC of 17 months and 11 months, respectively. Also overall survival (OS) shows a benefit for RCT (p = 0.016), with a median survival of 23 months for RCT and 16 months for RT. However, the benefit in SLC and OS is not seen in hypopharyngeal carcinomas. In a multivariate analysis of oropharyngeal cancer patients, p-Hb levels lower than 12.7 g/dL resulted in lower SLC compared with higher p-Hb levels up to 13.8 g/dL. P-Hb levels >13.8 g/dL did not further improve SLC. CONCLUSIONS: Hyperfractionated-accelerated RCT is superior to hf-acc RT in oropharyngeal carcinomas. P-Hb levels >13.8 g/dL do not further improve SLC.

Adult↗

PubMed2006

Popperian epidemiology and the logic of bi-conditional modus tollens arguments for refutational analysis of randomised controlled trials.

Popperian epidemiology is a biomedical science tool based on the hypothesis-deductive method and the falsifiability of scientific hypotheses. This article explores the applicability of the refutationist logic tools in the analysis of a randomised controlled trial (RCT), the randomised Aldactone evaluation study (RALES). This was carried out by using bi-conditional modus-tollens arguments of the type (i) P-then-Q(n) and (ii) Q(n)-If-X(P), X(P) being a set of potential falsifiers of Q(n) as part of the explicit falsity-content of P. In this model, P is the main hypothesis and Q(n) one or more logical predictions to be tested. The X(P) argument represents inclusion criteria, exclusion criteria and conditional criteria of the RCT so every P-then-X(P) argument should be fulfilled in canonical form to corroborate P-then-Q(n). Thus, falsifiability of a RCT would be determined by the empirical content of the conditional argument Q(n)-If-X(P) and its external validity would be determined by the empirical content of X(P). In this way it would be possible to mathematically assess the external validity of a RCT if the observational predicates of the X(P) argument in a given population are known. According to this popperian model, applicability of the RCT results to clinical practice implies transferring of all its empirical content, in other words, the totality of its truth and falsity contents. Thus, to ignore the explicit falsity-content of a RCT such as RALES may jeopardise its potential benefits in clinical practice as suggested by recent studies.

Clinical Trials as Topic↗

PubMed1983

Involvement of the domains of histones H1 and H5 in the structural organization of soluble chromatin.

We have studied in reconstitution experiments the conditions under which peptides derived from histones H1 and H5 are bound in chromatin and to what extent they are involved in the organization of chromatin fibers. The fragments of rat liver histone H1 (rH1) and chicken erythrocytes H1 (cH1) and H5 (cH5) used were the globular domains (rG-H1, cG-H1, cG-H5), the globular domain and the N-terminal tail (rCT-N), about half of the globular domain and the C-terminal tail (rNBS-C) and the C-terminal tail (rCT-C). Fragments containing the C-terminal tail (rNBS-C and rCT-C) dissociate from H1-depleted rat liver chromatin at 300 mM-NaCl and above (similar to uncleaved H1) and fragments lacking the C-terminal tail (rG-H1 and rCT-N) dissociate between 100 and 200 mM-NaCl. This suggests that at putative physiological ionic strengths the binding of rH1 is dominated by its C-terminal tail, whereas the globular region and the N-terminal tail might only be loosely bound or not bound at all and by this modulate chromatin structure. The globular domain of cH5 binds more tightly than that of the chicken and rat H1 and is only partially released at 200 mM. Since in the transcriptionally silent erythrocytes of birds H5 replaces H1 to a large extent, we suggest that the globular domain of H1 serves as a temporary seal and that of H5 as a permanent seal of the nucleosome. All the H1 and H5 peptides tested condensed and precipitated chromatin and H1-depleted chromatin: rNBS-C and rCT-C at lower peptide per nucleosome ratios than rG-H1, cG-H1 and rCT-N. At about one peptide per nucleosome none of the H1 fragments induced condensation similar to that of native chromatin. At a peptide per nucleosome ratio close to the point of precipitation, all H1 fragments, but not poly-L-lysine, induced similar compact forms which were fiberlike, although more irregular than the compact fibers of native chromatin. These reconstitution experiments suggest that both halves of H1 as well as the globular domain by itself are involved and capable in forming higher-order chromatin structures. Details of these structures are not known.

Animals↗

PubMed2000

Effect of dietary omega-3 fatty acids and chronic ethanol consumption on reverse cholesterol transport in rats.

We previously showed that chronic ethanol feeding leads to a decrease of apolipoprotein E (apoE) in high-density lipoprotein (HDL), whereas supplementing this diet with 2.8% of total dietary calories as omega3-fatty acids (omega3FAs) restores HDL-apoE to the control values. Since HDL containing apoE plays a major role in reverse cholesterol transport (RCT), we measured the effects chronic ethanol intake and omega3-FAs on RCT in the present study. Four groups of rats, control normal fat (CN), alcohol-normal fat (AN), control omega3FA fat (CF), and alcohol-omega3FA fat (AF), were fed their respective diets for 8 weeks, after which hepatocytes and HDLs from each group were evaluated for RCT capacity (cholesterol efflux from macrophages and uptake by liver cells). Compared with the control diet (CN), chronic ethanol (AN) feeding inhibited the cholesterol efflux capacity of HDL by 21% (P < .01), whereas omega3FA feeding (2.8% of total dietary calories) stimulated this capacity by 79% (P < .01) and 25% (P < .01) in CF and AF rats, respectively. With respect to cholesterol uptake by the liver, there were no significant 3-way or 4-way interactions between the 4 factors, HDL-alcohol, HDL-fish oil, hepatocyte-alcohol, and hepatocyte-fish oil. The main effects for HDL-alcohol, HDL-fish oil, and hepatocyte-alcohol were all highly significant (P = .0001, .0001, and .007, respectively). There was a significant HDL-alcohol and HDL-fish oil interaction (P = .0001). Hepatocyte-alcohol was not a factor in any 2-way interactions. Our study indicates no evidence of an interaction between the effects of omega3FAs and the effects of alcohol on hepatocytes in terms of RCT function. Thus, feeding as little as 2.8% of the total dietary calories as omega3FA not only restored the impaired RCT function of HDL caused by chronic ethanol intake, but also enhanced by severalfold the ability of HDL to promote RCT even in normal animals.

Administration, Oral↗

PubMed2002

Apoptosis as a cellular predictor for histopathologic response to neoadjuvant radiochemotherapy in patients with rectal cancer.

BACKGROUND: Tumor shrinkage by preoperative radiochemotherapy (RCT) can markedly improve surgery in locally advanced (T4) rectal cancer with clear resection margins and may enable sphincter preservation in low-lying tumors. However, tumor response varies considerably, even among tumors treated according to the same protocol. If one is able to identify patients with highly radio-responsive tumors at the time of diagnosis, a selective and individualized policy of preoperative RCT might be pursued. METHODS: The apoptotic index (AI), Ki-67, p53, and bcl-2 were evaluated by immunohistochemistry on pretreatment biopsies from 44 patients treated uniformly according to a prospective neoadjuvant RCT protocol (CAO/AIO/ARO-94). Treatment response was assessed histopathologically in the resected surgical specimen, using a five-point grading system. Expression of each marker was correlated with tumor response and relapse-free survival after curative surgery. RESULTS: Tumors with complete (n = 3) or good (n = 28) response to RCT showed significantly higher pretreatment levels of apoptosis (mean AI: 2.06%) than tumors with moderate (n = 7), minimal (n = 5), or no regression (n = 1) from RCT (AI: 1.44%, p = 0.003). The AI was significantly related to Ki-67 (p = 0.05), but not to p53 and bcl-2 status. Tumor regression and AI best predicted relapse-free survival after combined modality treatment and curative surgery. CONCLUSION: Spontaneous apoptosis in rectal cancer may serve as an important predictor of tumor regression from RCT in rectal cancer and as a significant prognosticator of relapse-free survival. Thus, this molecular marker may finally help to tailor therapy with regard to (neo-) adjuvant treatment of rectal cancer.

Adult↗

PubMed1998

Efficacy of radiochemotherapy with platin derivatives compared to radiotherapy alone in organ-sparing treatment of bladder cancer.

PURPOSE: Presently, for muscle-invasive bladder cancer, radical cystectomy is considered to be the standard treatment. Bladder preservation, in the interest of quality of life, is secondary to the primary treatment goal of curing the patient. We present a 14-year multivariate analysis of prognostic factors influencing survival and bladder preservation after transurethral resection of the bladder (TURB) and radiotherapy (RT) +/- chemotherapy. METHODS AND MATERIALS: From May 1982 to May 1996, sequential cohorts of 333 patients with bladder cancer (mean age: 66 years) were treated by either RT alone (128 patients), or with platin-based concomitant radiochemotherapy (RCT, 205 patients) after TURB. Patients (282) with muscle-invasive or T1 high-risk cancers (Grade III, residual tumor after TURB, multifocality, tumor diameter > 5 cm, associated Tis or Ta, multiple recurrences or lymph node metastases), who received a minimal target dose of 45 Gy were selected for analysis (med. follow-up = 7.5 years): after October 1985, 115 patients received cisplatin (25 mg/m2) and 69 patients carboplatin (65 mg/m2) before every treatment fraction (1.8 Gy) on Days 1-5 and 29-33 of conventional fractionated RT. RESULTS: Complete remission rate was 20% (55 of 282 patients) after radical TURB, 57% (56 of 98) after TURB plus postoperative RT, and 80% (145 of 181 patients) after TURB plus RCT (85% after concomitant cisplatin and 70% after RCT plus carboplatin). These differences were significant in multivariate analysis (p = 0.003-0.05). The strongest impact on initial response had T-category (p < 0.0001) and R-status after TURB (p < 0.0003). Cause-specific survival (CSS) was 59 and 43% after 5 and 10 years; 79% of patients survived with preserved bladder. Five-year CSS after RT, RCT-Cis, and RCT-Carbo was 40, 64, and 54%, 10-year CSS 31, 48, and 27%, respectively (p = 0.04-0.045, univariate). R-status after TURB was the only independent prognostic factor for survival and bladder preservation. For relapsed patients after cystectomy, the 5- and 10-year CSS were 40 and 33%. CONCLUSIONS: TURB followed by RT/RCT is an alternative treatment option to primary cystectomy for patients with muscle-invading bladder cancer. Compared to historic controls, the addition of cisplatin or carboplatin leads to significantly more complete remissions and better survival. Survival rates are similar to those achieved by primary cystectomy and possibly even better for selected subjects, such as patients with T3b and T4 tumors. Cystectomy should be restricted to only those patients who fail after RCT.

Adult↗