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PubMed1997

Implications of socio-cultural contexts for the ethics of clinical trials.

BACKGROUND: Health technology assesment (HTA) requires scientifically rigorous experimentation involving patients as subjects. HTA itself is required so that treatment given to patients will be both effective and efficient; this requirement is itself ethical in nature. At the same time it is essential that the methods used in HTA are ethically sound. Most healthcare researchers agree that the most effective and soundest method for assessing treatments is the randomised controlled trial (RCT). However, some researchers believe that the RCT is unethical, either in essence, or for use in some forms of medical research and HTA. Furthermore, many patients seem unable to understand the principles and purposes of the RCT, a factor which is highly detrimental for the validity of informed consent. Informed consent is the key to the ethics of medical research, both in most theories and in all codes of research conduct. Many RCTs therefore risk being unethical in practice, even if ethical in principle. AIM OF REPORT: To survey the main objections to the RCT and its alternatives. To assess the philosophical and methodological basis of these objections, and of the methods recommended for addressing them. To identify areas where objections are founded in social or cultural factors normally overlooked in ethical argument about the RCT methodology. To identify alternative arguments or methods which might resolve ethical conflicts in this area. HOW THE RESEARCH WAS CONDUCTED: The methods used were adapted from systematic reviews in medicine. Systematic searches of Medline, Psychlit and Sociofile CD-ROM databases; hand-searches of the major journals in general medicine and surgery, medical ethics and philosophy; and searches of books were carried out. The literature survey was restricted to articles published or abstracted in English. A database of the most relevant and useful materials was compiled, and is accessible on the Internet (http://www.liv.ac.uk/sdthomps/page1.html). RESEARCH FINDINGS: UNDERSTANDING RCTS AND THEIR ALTERNATIVES: There is some evidence of difficulty in understanding the aims and methods of RCTs, and some disquiet about elements of the RCT methodologies. These objections are well known and much discussed, and concern the use of placebo, the continuation of trials after significant differentials in benefit or harm are apparent, and randomisation. CULTURAL OR RELIGIOUS OBJECTIONS: There was an absence of evidence of cultural or religious objections to randomisation, placebo or other kinds of controlled prospective trials. This most likely reflects an absence of research rather than absence of objections. (ABSTRACT TRUNCATED)

Cultural Diversity↗
PubMed2000

Techniques for pelvic surgery in subfertility.

BACKGROUND: Since the advent of in-vitro fertilisation (IVF) the role of infertility surgery has diminished. This type of surgery is still however widely performed.and there are many different surgical techniques that can be used to repair blocked or damaged Fallopian tubes. Most evidence in this area comes from uncontrolled series. OBJECTIVES: To evaluate surgical techniques for the treatment of tubal infertility (adhesiolysis, salpingostomy, surgery for proximal tubal occlusion, reversal of sterilisation). SEARCH STRATEGY: This review has drawn on the search strategy developed for the Subfertility Group as a whole. Relevant trials were identified from the Group's Register of Controlled Trials. SELECTION CRITERIA: All randomised controlled trials investigating an aspect of infertility surgery technique. Non-randomised data were included for the following topics 1) The role of infertility surgery versus no treatment 2) The role of infertility surgery versus alternative treatments, 3) the role of magnification, 4) The role of the CO2 laser at infertility surgery, 5) the role of operative laparoscopy to perform infertility surgery. Non- RCT data were excluded if :- i) The treatment and control groups differed significantly ii) The treatment and control groups were operated by a different team or in a different institute iii) Where pregnancy outcome data were not given. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the first 2 authors. Differences of opinion were registered and resolved by consensus with the senior author (RL). Two by two tables were generated for each trial for the dichotomous outcome of pregnancy and the effects on pregnancy rate of each study is expressed as an odds ratio with 95% confidence intervals. MAIN RESULTS: 1) INFERTILITY SURGERY VERSUS NO TREATMENT One non RCT compared open adhesiolysis versus no treatment and found significantly more pregnancies in the treatment group compared with the control group. 2) INFERTILITY SURGERY VERSUS ALTERNATIVE TREATMENTS. No RCTs investigated the role of infertility surgery compared with In vitro fertilisation (IVF). There were no studies comparing tubal surgery for proximal tubal occlusion versus hysteroscopic or radiologically controlled recannulation. 3) MAGNIFICATION FOR INFERTILITY SURGERY There was a non significant reduction in pregnancy rate when the operating microscope (magnification x4-x16) was used rather than Loupes (magnification x2-x4.5) in the only RCT to study this. One RCT randomised patients to microsurgery versus a macrosurgical technique involving a prosthesis. There were more pregnancies in the microsurgery group, but this was not significant, and the trial consisted of only 18 participants. All the non-RCT studies comparing microsurgery with macrosurgery had a historical control group. Meta-analysis of studies investigating the role of magnification for adhesiolysis and for salpingostomy revealed a statistically significant increase in pregnancy rates and reduction in ectopic pregnancy rates for microsurgery versus macrosurgery for both procedures. For reversal of sterilisation there was a significant improvement in term pregnancy rates, and a non significant reduction in ectopic rates There was no significant difference between microsurgical and macrosurgical treatment of proximal tubal occlusion for any outcome. 4) THE USE OF LASER AT INFERTILITY SURGERY Two RCTs investigated the use of the CO2 laser at infertility surgery. There was no significant difference in pregnancy outcome after adhesiolysis, or salpingostomy. Two non randomised studies also investigated the role of the laser. Overall there was no significant difference using the CO2 laser compared with standard techniques for adhesiolysis, salpingostomy or reversal of sterilisation. 5) LAPAROSCOPIC INFERTILITY SURGERY Four studies investigated the use of laparoscopic techniques for infertility surgery. There were no RCTs. One study compared laparoscopic versus open

Fallopian Tube Diseases↗
PubMed2004

Cognitive behaviour therapy for schizophrenia.

BACKGROUND: Cognitive behavioural therapy (CBT) is now a recommended treatment for people with schizophrenia. This approach helps to link the person's feelings and patterns of thinking which underpin distress. OBJECTIVES: To review the effects of CBT for people with schizophrenia when compared to standard care, specific medication, other therapies and no intervention. SEARCH STRATEGY: This 2004 update built on past work by searching the Cochrane Schizophrenia Groups' Register of Trials (January 2004). We inspected all references of the selected articles for further relevant trials. SELECTION CRITERIA: All relevant clinical randomised trials of cognitive behaviour therapy for people with schizophrenia-like illnesses. DATA COLLECTION AND ANALYSIS: Studies were reliably selected and assessed for methodological quality. Two reviewers, working independently, extracted data. We analysed dichotomous data on an intention-to-treat basis and continuous data with 65% completion rate are presented. Where possible, for dichotomous outcomes, we estimated a relative risk (RR) with the 95% confidence interval (CI) along with the number needed to treat/harm (NNT/H). MAIN RESULTS: 30 papers described 19 trials. CBT plus standard care did not reduce relapse and readmission compared with standard care (long term 4 RCTs, n=357, RR 0.8 CI 0.5 to 1.5), but did decrease the risk of staying in hospital (1 RCT, n=62, RR 0.5 CI 0.3 to 0.9, NNT 4 CI 3 to 15). CBT helped mental state over the medium term (2 RCTs, n=123, RR No meaningful improvement 0.7 CI 0.6 to 0.9, NNT 4 CI 3 to 9) but after one year the difference was gone (3 RCTs, n=211, RR 0.95 CI 0.6 to 1.5). Continuous measures of mental state (BDI, BPRS, CPRS, MADRS, PAS) do not demonstrate a consistent effect. When compared with supportive psychotherapy, CBT had no effect on relapse (1 RCT, n=59, RR medium term 0.6 CI 0.2 to 2; 2 RCTs, n=83, RR long term 1.1 CI 0.5 to 2.4). This also applies to the outcome of 'No clinically meaningful improvements in mental state' over the same time periods (1 RCT, n=59, RR medium term 0.8 CI 0.6 to 1.1; 2 RCT, n=100, RR long term 0.9 CI 0.8 to 1.1). When CBT was combined with a psychoeducational approach there was no significant reduction of readmission rates relative to standard care alone (1 RCT, n=91, RR 0.9 CI 0.6 to 1.4). REVIEWERS' CONCLUSIONS: CBT is a promising but under evaluated intervention. Currently, trial-based data supporting the wide use of CBT for people with schizophrenia or other psychotic illnesses are far from conclusive. More trials are justified, especially in comparison with a lower grade supportive approach. These trials should be designed to be both clinically meaningful and widely applicable.

Cognitive Behavioral Therapy↗
PubMed2000

Minocycline for acne vulgaris: efficacy and safety.

BACKGROUND: Minocycline is a tetracycline antibiotic that is commonly used in the treatment of moderate to severe acne vulgaris. Although it is more convenient for patients to take than first-generation tetracyclines, as it only needs to be taken once or twice a day and can be taken with food, it is more expensive. Concerns have also been expressed over its safety following the deaths of two patients taking the drug. There is a lack of consensus among dermatologists over the relative risks and benefits of minocycline. As most acne prescribing is undertaken by general practitioners, it is important that guidelines issued to them are based on the best available evidence rather than personal judgements. OBJECTIVES: To collate and evaluate the evidence on the clinical efficacy of minocycline in the treatment of inflammatory acne vulgaris. Specific objectives were to compare the efficacy of minocycline with other drug treatments for acne and to collate information on the incidence of adverse drug reactions. SEARCH STRATEGY: Randomised controlled trials (RCTs) of minocycline for acne vulgaris were identified by searching the following electronic databases; MEDLINE, EMBASE, Biosis, Biological Abstracts, International Pharmaceutical Abstracts, Cochrane Skin Group's Trial Register, Theses Online, BIDS ISI Science Citation Index and Bids Index to Scientific and Technical Proceedings. Other strategies used were scanning the references of articles retrieved, hand-searching of major dermatology journals and personal communication with trialists and drug companies. SELECTION CRITERIA: To be eligible for the review, studies had to be RCTs comparing the efficacy of minocycline at any dose to active or placebo control, in subjects with inflammatory acne vulgaris. Diagnoses of papulo-pustular, polymorphic and nodular acne were also accepted. Trials were not excluded on the basis of language. DATA COLLECTION AND ANALYSIS: 27 randomised controlled trials met the inclusion criteria and were included in this review. The comparators used were placebo (2 studies), oxytetracycline (1), tetracycline (6), doxycycline (7), lymecycline (2), topical clindamycin (3), topical erythromycin/zinc (1), cyproterone acetate/ ethinyloestradiol (1), oral isotretinoin (2), topical fusidic acid (1) and there was one dose response study. One study is ongoing and it remains to be clarified whether one further study is a RCT. Major outcome measures used in the trials included lesion counts, acne grades/severity scores, doctors' and patients' global assessments, adverse drug reactions and drop out rates. The quality of each study was assessed independently by two assessors and an effect size calculated where possible. MAIN RESULTS: The trials were generally small and of poor quality and in many cases the published reports were inadequate for our purpose. Pooling of the studies was not attempted due to the lack of common outcome measures and endpoints and the unavailability of some primary data. Although minocycline was shown to be an effective treatment for acne vulgaris, in only two studies was it found to be superior to other tetracyclines. Both of these were conducted under open conditions and had serious methodological problems. A third study showed it to be more effective than 2% fusidic acid, applied topically, against inflammatory lesions in mild to moderate acne. Differences in the way adverse drug reactions were identified could have accounted for the wide variation between studies in numbers of events reported. This meant that no overall evaluation could be made of incidence rates of adverse events associated with minocycline therapy. No RCT evidence was found to support the benefits of minocycline in acne resistant to other therapies and the dose response has only been evaluated up to eight weeks of therapy. (ABSTRACT TRUNCATED)

Acne Vulgaris↗
PubMed2004

Aripiprazole for schizophrenia.

BACKGROUND: Treatment of people with schizophrenia using older typical antipsychotic drugs such as haloperidol can be problematic. Many fail to respond and more experience disabling adverse effects. Aripiprazole is said to be one of a new generation of atypical antipsychotics with good antipsychotic properties and minimal adverse effects. OBJECTIVES: To evaluate the effects of aripiprazole for people with schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY: The reviewers searched the Cochrane Schizophrenia Group's Register (May 2003) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. References of all identified studies were inspected for further trials. The authors contacted relevant pharmaceutical companies, the FDA and authors of trials for additional information. SELECTION CRITERIA: All clinical randomised trials comparing aripiprazole with placebo, typical or atypical antipsychotic drugs for schizophrenia and schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For homogenous dichotomous data we calculated random effects, relative risk (RR), 95% confidence intervals (CI) and, where appropriate, numbers needed to treat (NNT) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD). MAIN RESULTS: Despite the fact that 4125 people participated in ten randomised aripiprazole studies, we were unable to extract any usable data on death, service outcomes, general functioning, behaviour, engagement with services, satisfaction with treatment; economic outcomes or cognitive functioning. Study attrition was very large and data reporting poor. Compared with placebo, aripiprazole significantly decreased relapse in both the short and medium term (n=300, 1 RCT, RR 0.66 CI 0.53 to 0.81, NNT 5 CI 4 to 8). It also produced better compliance with study protocol (n=1348, 5 RCTs, RR 0.66 CI 0.49 to 0.88, NNT 15 CI 10 to 41). Aripiprazole may decrease prolactin levels below that expected from placebo (n=305, 1 RCT, RR 0.32 CI 0.13 to 0.81, NNT 14 CI 11 to 50). Compared with typical antipsychotics there were no significant benefits for aripiprazole with regards to global state, mental state, quality of life or leaving the study early. Both groups reported similar rates of adverse effects, including akathisia (RR 0.44 CI 0.17 to 1.12) and general extrapyramidal effects (RR 0.53 CI 0.18 to 1.53). Aripiprazole did however cause more insomnia than perphenazine (n=300, 1 RCT, RR 2.23 CI 1.57 to 3.18, NNH 4 CI 3 to 9) and less need for antiparkinson drugs than 10-20mg/day haloperidol (n=1854, 4 RCTs, RR 0.45 CI 0.33 to 0.60, NNT 4 CI 3 to 5). When compared with olanzapine and risperidone, aripiprazole was no better or worse on outcomes of global state and leaving the study early. The rates of adverse effects were also similar, with the exception of less elevation of prolactin (n=301, 1 RCT, RR 0.04 CI 0.02 to 0.08, NNT 2) and less prolongation of the average QTc (30mg/day) (n=200, 1 RCT, WMD -10.0, CI -16.99 to -3.01) compared with risperidone. REVIEWERS' CONCLUSIONS: Aripiprazole may be effective for the treatment of schizophrenia, but it is not much different from typical antipsychotics and atypical antipsychotics with respect to treatment response, efficacy or tolerability. In comparison with typical antipsychotics, aripiprazole may have a higher risk of insomnia, but in comparison to atypical antipsychotics, less risk of raised prolactin and prolongation of the QTc interval. Clearly reported pragmatic short, medium and long term randomised controlled trials should be carried out to determine its position in everyday clinical practice.

Antipsychotic Agents↗
PubMed2006

Aripiprazole for schizophrenia.

BACKGROUND: Treatment of people with schizophrenia using older typical antipsychotic drugs such as haloperidol can be problematic. Many fail to respond to these older antipsychotics and more people experience disabling adverse effects. Aripiprazole is said to be one of a new generation of atypical antipsychotics with good antipsychotic properties and minimal adverse effects. OBJECTIVES: To evaluate the effects of aripiprazole for people with schizophrenia and schizophrenia-like psychoses. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (September 2005) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. We inspected references of all identified studies for further trials. We contacted relevant pharmaceutical companies, the FDA and authors of trials for additional information. SELECTION CRITERIA: All clinical randomised trials comparing aripiprazole with placebo, typical or atypical antipsychotic drugs for schizophrenia and schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For homogenous dichotomous data we calculated random effects, relative risk (RR), 95% confidence intervals (CI) and, where appropriate, numbers needed to treat (NNT) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD). MAIN RESULTS: Despite the fact that 7110 people participated in fifteen randomised aripiprazole studies, we were unable to extract any usable data on death, service outcomes, general functioning, behaviour, engagement with services, satisfaction with treatment; economic outcomes or cognitive functioning. Study attrition was very large and data reporting poor. Compared with placebo, aripiprazole significantly decreased relapse in both the short and medium term (n=300, 1 RCT, RR 0.66 CI 0.5 to 0.8, NNT 5 CI 4 to 8). It also produced better compliance with study protocol (n=2271, 8 RCTs, RR 0.72 CI 0.5 to 0.97, NNT 26 CI 16 to 239). Aripiprazole may decrease prolactin levels below that expected from placebo (n=305, 1 RCT, RR 0.32 CI 0.1 to 0.8, NNT 14 CI 11 to 50). Compared with typical antipsychotics there were no significant benefits for aripiprazole with regards to global state, mental state, quality of life or leaving the study early. Both groups reported similar rates of adverse effects, with the exception of akathisia (n= 955 RR 0.31 CI 0.2 to 0.6, NNT 20 CI 17 to 32) and the need for antiparkinson medication (n=1854, 4 RCTs, RR 0.45 CI 0.3 to 0.6, NNT 4 CI 3 to 5) which were lower in those receiving aripiprazole. When compared with olanzapine and risperidone, aripiprazole was no better or worse on outcomes of global state and leaving the study early. The rates of adverse effects were also similar, with the exception of less elevation of prolactin (n=301, 1 RCT, RR 0.04 CI 0.02 to 0.1, NNT 2 CI 1 to 2.5) and less prolongation of the average QTc (30 mg/day) (n=200, 1 RCT, WMD -10.0, CI -16.99 to -3.0) compared with risperidone. When compared with standard care (mixed group receiving typical and atypical antipsychotics) one aripiprazole study did have significantly less people not responding to treatment (n=1599, RR 0.70 CI 0.7 to 0.8, NNT 5 CI 4 to 6 ), not satisfied with care (n=1599, RR 0.62 CI 0.6 to 0.7, NNT 4 CI 4 to 5) and less people leaving the study early (n=1599, 1 RCT, RR 0.81 CI 0.7 to 0.9, NNT 13 CI 8 to 39). Results from the five new papers identified from the updated review search, did not significantly alter the main results or conclusions of the original review. AUTHORS' CONCLUSIONS: Aripiprazole may be effective for the treatment of schizophrenia, but it does not differ greatly from typical and atypical antipsychotics with respect to treatment response, efficacy or tolerability. In comparison with typical antipsychotics, aripiprazole may have a lower risk of akathisia, and in comparison to atypical antipsychotics, less risk of raised prolactin and prolongation of the QTc interval. Clearly reported pragmatic short, medium and long term randomised controlled trials should be undertaken to determine its position in everyday clinical practice.

Antipsychotic Agents↗
PubMed2026

Enhancing Evidence Generation by Linking Randomized Clinical Trials to Real-World Data: The INVESTED-Medicare Linkage Study.

Real-world evidence (RWE) derived from real-world data (RWD) can complement randomized controlled trials (RCTs), yet the validity of RWD relative to RCT data remains insufficiently characterized. We obtained post hoc consent and linked individual participant data from the US-based INVESTED trial (2016-2019) with Medicare fee-for-service claims (2012-2020) to validate demographic factors, baseline characteristics (using 183-, 365-, and 730-day lookback periods) and outcomes, and to assess post-trial events. Among 5260 trial participants, 126 were enrolled and eligible for linkage. Among 115 participants with demographic information available from Medicare enrollment files, agreement between RCT- and RWD-based demographic factors was high: only one major age discrepancy, 100% agreement for sex, and an overall agreement of 0.89 for race. Participants with Medicare claims data (n = 65) were older and more likely to be White compared with the overall RCT population. For the 365-day lookback period, baseline comorbidities showed high sensitivity (median 0.80) and specificity (0.89), as did medication use (sensitivity 1.00, specificity 0.88). Lengthening the lookback period to 730 days increased sensitivity but decreased specificity, whereas shortening to 183 days decreased sensitivity but increased specificity. Clinical outcomes showed high specificity (0.88-0.94) but low sensitivity (0.18-0.50). Among those with Medicare coverage beyond the trial end date (n = 45), 22% experienced cardiopulmonary, 18% cardiovascular, and 7% heart failure (HF) hospitalizations, highlighting the value of RWD for extending RCT evidence. Proactive planning of future RCT-RWD linkage initiatives can improve the efficiency of linkage studies, leading to more actionable results.

Journal Article↗
PubMed2004

Historiography taking issue: analyzing an experiment with heroin abusers.

This article discusses the predicament of historians becoming part of the history they are investigating and illustrates the issue in a particular case. The case is that of the randomized controlled trial (RCT)-more specifically, its use for testing the effects of providing heroin to severe heroin abusers. I counter the established view of the RCT as a matter of timeless logic and argue that this research design was developed in the context of administrative knowledge making under twentieth-century economic liberalism of which it epitomizes some central values. I also argue that the applicability of the RCT depends on the degree to which its advocates can define the issue to be studied according to its inherent values. Next, I demonstrate how advocates of an RCT with heroin provision in the Netherlands steered the political discussion on heroin provision and how the values of economic liberalism also shaped the results of the Dutch maintenance experiment. In addition, I relate how my analysis of this experiment became part of political debates in the Netherlands. Contrary to my intentions, adversaries of heroin maintenance used my critique on the heroin RCT as an argument against heroin maintenance. Such risks are inherent to historiography and sociology of science aiming at practical relevance while challenging treasured scientific beliefs. I conclude that it still seems better to expose arguments on unjustified certainties than to suppress them for strategic reasons.

Heroin↗
PubMed1993

Clinical studies in surgical journals--have we improved?

A critical appraisal of all clinical studies published in 1980 and 1990 in three surgical journals--Diseases of the Colon and Rectum (DCR), Surgery (SURG), and the British Journal of Surgery (BJS)--was made to ascertain the frequency with which various research designs appeared, the standard of individual clinical studies, and a comparison of changes in the past decade. Clinical studies were classified into case studies or comparative studies. Comparative studies included randomized controlled trials (RCT), nonrandomized controlled trials, retrospective cohorts, and case-control studies. A 10-point index score (range, 0-10) was used to assess the comparative studies. A sample of articles was analyzed for interobserver and intraobserver variation, with strong agreement between reviewers for classification of trials (unweighted kappa, 0.87) and index scores (0.67). Of 1,481 articles reviewed, 1,060 were classified as clinical studies. Sixteen percent of all clinical studies were comparative studies in 1980, compared with 17 percent in 1990. Of these, 7 percent were RCT in both years. In 1980, 6 percent of clinical studies in DCR were comparative studies, 19 percent in BJS, and 18 percent in SURG. In 1990, 11 percent, 18 percent, and 18 percent, respectively, were comparative studies. In 1980, the proportion of RCT in DCR was 0 percent, in BJS 12 percent, and in SURG 4 percent, compared with 3 percent, 8 percent, and 8 percent, respectively, in 1990. Overall, 52 of 76 (68 percent) RCT were published in BJS. The standard of comparative studies increased overall from 5.49 to 6.04 (P = NS), and that of RCT increased from 7.06 to 7.70 (P = NS). The standard of comparative studies in DCR in 1980 was lower than those in BJS (P < 0.001) and SURG (P < 0.001). The standard of comparative studies in DCR improved from 1.67 in 1980 to 5.47 in 1990 (P < 0.001). There was no significant difference in the standard of comparative studies among the three journals in 1990. In conclusion, there has been no overall increase in the proportion of stronger clinical trial designs in the journals reviewed. A small increase seen in the overall standard of comparative studies was not statistically significant.

Case-Control Studies↗
PubMed2004

[Influence of preoperative (hyperthermic) radiochemotherapy on manometric anal sphincter function in locally advanced rectal cancer].

BACKGROUND AND PURPOSE: Preoperative radiochemotherapy (RCT) followed by curative surgery is a well-accepted therapeutic option in the treatment of advanced rectal cancer. Usually, the anal sphincter is located in the irradiation area of a preoperative RCT regime. The aim of this study is to evaluate the influence of preoperative RCT on anal sphincter function. PATIENTS AND METHODS: Between 1994 and 2000, 102 patients with rectal cancer stage uT3/uT4 were analyzed. All patients underwent radiotherapy with 45 Gy (5 x 1.8 Gy) including two cycles of 5-fluorouracil (5-FU)/leucovorin (folinic acid) chemotherapy. 46 patients were treated additionally with up to five sessions of locoregional hyperthermia. The sphincter function was analyzed by perfusion manometry before preoperative therapy and 4 weeks after pretreatment had been finished. For statistics, the Wilcoxon signed rank test and Mann-Whitney U-test were used (SPSS 9.0 for Windows((R))). RESULTS: The mean value of all 102 patients showed a significant reduction of the mean maximum resting pressure from 97 to 89 mmHg (p = 0.02). For the mean maximal squeeze pressure no significant difference could be shown (178 vs. 176 mmHg). For patients with distal (</= 7.5 cm from anal verge) tumors the difference was highly significant (92 vs. 79 mmHg). Locoregional hyperthermia had no additional influence on sphincter function. CONCLUSION: Preoperative RCT impairs sphincter function especially in patients with distal tumors. In addition, RCT could have a negative influence on the continence of patients who received sphincter-preserving surgery.

Anal Canal↗
PubMed2004

Neoadjuvant radiochemotherapy in locally advanced gastric carcinoma.

BACKGROUND AND PURPOSE: Gastric carcinoma is characterized by a high rate of local recurrences and distant metastases and is often not resectable due to locally advanced stage. The aim of this study was to examine feasibility and effectiveness of neoadjuvant radiochemotherapy (RCT) for locally advanced, primarily nonresectable gastric carcinoma and to achieve curative resection. PATIENTS AND METHODS: 21 patients with locally advanced gastric cancer located in cardia (n = 17) and corpus (n = 4; seven cT3; 14 cT4; 18 cN+; all cM0) with a median age of 61 years were scheduled to receive neoadjuvant RCT. Therapy consisted of a conventionally fractionated, conformal radiotherapy using the shrinking-field technique (1.8 Gy to 45 Gy + 5.4 Gy) and chemotherapy using cisplatin (20 mg/m(2), d1-5, 29-33), 5-fluorouracil (5-FU; 800 mg/m(2), d1-5, 29-33) or paclitaxel (135 mg/m(2), d1, 29). 4-6 weeks after completion of RCT, surgery was performed whenever feasible. RESULTS: Hematologic toxicity was moderate with grade 3 leukopenia in 10/21 patients and grade 3 thrombopenia in 5/21 (CTC). Nonhematologic toxicities consisted of 5/21 cases of fever as well as one fungal sepsis. Following RCT, tumors were classified resectable in 16/21 patients (76%); 12/21 patients (58%) were operated on, 11/12 achieved clear margins (R0). Response was as follows: complete remission (CR) 3/21 (14%), partial remission 13/21 (62%), no change 3/21 (14%), systemic progressive disease (PD) 2/21 (10%). The median survival and the 2-year survival rates were 18 months and 42%, respectively, for the patients following R0 resections as compared to 10 months and 0% for the remaining patients (p = 0.035). Local control (4 years) for patients following R0 resection was 89%. CONCLUSION: Neoadjuvant RCT is feasible and locally highly effective but must be further investigated involving a higher number of patients.

Adult↗
PubMed2006

Concurrent radiochemotherapy of locally recurrent or advanced sarcomas of the uterus.

BACKGROUND: Uterine sarcomas are rare tumors. Until now, no data on the treatment of recurrent or advanced uterine sarcomas using concurrent radiochemotherapy (RCT) has been available. PATIENTS AND METHODS: From 01/1997 to 03/2004, seven patients with locally recurrent (n = 6) or locally advanced uterine sarcomas (n = 1) received concurrent RCT after tumor surgery (R1/2 resection in 3/7 patients). A total radiation dose of 45 Gy was applied in single doses of 1.8 Gy using an external-beam technique; in addition, three to four intracavitary doses of 5 Gy were applied. Concurrent chemotherapy was generally administered as follows: 1.2 g/m(2) ifosfamide on days 1-5 and 29-33 in combination with 50 or 40 mg/m(2) adriamycin on days 2 and 30. 3/7 patients received further cycles of chemotherapy. The median follow- up was 35 months. RESULTS: All recurrences (before RCT) were localized either in the vagina or in or directly proximal to the vaginal stump. The main side effects of RCT were hemotoxicity (grade 3: n = 3/7; grade 4: n = 4/7; neutropenic fever n = 1/7) and diarrhea (grade 3: n = 5/7). At the median follow-up (35 months), 4/7 patients had recurrences (one local recurrence; one lymph node recurrence outside the irradiated field, two distant metastases). Local control in the irradiated field was 80% +/- 18% after 3 years. Disease-free survival calculated according to Kaplan-Meier was 57% +/- 19% after 3 years. Presently, 5/7 patients are still alive, corresponding to a 3-year survival rate of 83% +/- 15%. CONCLUSION: Concurrent RCT shows good local effectiveness with a good long-term survival. Further evaluation in phase II studies is recommended.

Adult↗
PubMed1987

The experimental paradigm and observational studies of cause-effect relationships in clinical medicine.

The paradigm of the randomized clinical trial (RCT) is proposed as a heuristic that can serve as a unified approach to guide the design not just of cause-effect studies of therapy, but also of studies of the etiology of disease. Three themes are developed in detail: that variability in the scientific paradigm of the randomized trial results in a wide range of techniques and methods being employed for the RCT, and that this extensive variability in clinical trial methods contributes substantially to the occurrence of conflicting trial results; that the scientific validity of observational surrogates for the RCT could be enhanced if investigators designed observational studies by incorporating the principles inherent in the RCT; and that there are two distinctive and competing strategies for designing case-control studies. The traditional strategy views case-control designs as statistical acts of sampling for cases and controls, but ignores the scientific reasoning that should guide the performance of case-control research. The alternative strategy requires that case-control studies adhere to the principles inherent in the RCT.

Clinical Trials as Topic↗
PubMed1990

Prevalence and sequelae of sexual torture.

283 torture victims (135 examined by the Amnesty International [AI] Danish Medical Group, and 148 by the International Rehabilitation and Research Center for Torture Victims [RCT]) were questioned about methods of torture and subsequent sexual difficulties. Overall, the prevalence of sexual torture was 61% (women 80%, men 56%), but this was higher in the RCT than in the AI group. More Latin Americans than Europeans had been sexually tortured in the AI group. Prevalence of sexual difficulties was 32%, the RCT recording a significantly higher prevalence than the AI (43% vs 20%). Sexually tortured victims were more likely to have sexual difficulties (40%) than were non-sexually tortured victims (19%). Overall, there were more cases of sexual difficulties in victims from Africa and from Turkey/Middle East/Far East than in victims from Latin America and from Europe. In the RCT subsample, prevalence of sexual difficulties and anxiety was significantly higher in sexually tortured victims than in non-sexually tortured victims; the two groups were broadly similar with respect to depression and low self-esteem. Depressed victims and victims with low self-esteem were more likely to have sexual difficulties. In the RCT group, but not overall, prevalence of sexual difficulties was significantly associated with age but was independent of low self-esteem and of depression.

Adolescent↗
PubMed1995

The influence of clinical study design on cost-effectiveness projections for the treatment of gram-negative sepsis with human anti-endotoxin antibody.

PURPOSE: This study was performed to compare the effect of entry criteria, patient population, and study design on outcome and projected cost-effectiveness of human anti-endotoxin antibody (HA-1A). MATERIALS AND METHODS: Patients with suspected or documented gram-negative bacteremia (GNB) with sepsis syndrome or shock received HA-1A during an open-label protocol. The patient characteristics and outcome measures of this series were compared with those of a placebo-controlled randomized clinical trial (RCT) of HA-1A. Both data sets were subjected to three published cost-effectiveness models of anti-endotoxin therapy, which were derived from RCT data. RESULTS: One hundred thirty-one patients (43 with gram-negative bacteremia) received HA-1A during a 19-month open-label protocol. Comparison with the RCT results demonstrated greater severity of illness and higher 28-day mortality in the open-label protocol. When projected for open-label recipients, HA-1A was considerably less cost-effective than in the original projections based on RCT-derived data. This reduction in cost-effectiveness was consistent across all three models and their respective sensitivity analyses. CONCLUSIONS: Extrapolating cost-effectiveness from RCT-derived analyses to open-label usage may yield widely inaccurate projections because of only small differences in patient population and the drug administration protocol.

Aged↗
PubMed2004

Extended follow-up of patients randomly assigned in the Angiotensin-converting enzyme inhibition Post-Revascularization Study (APRES).

BACKGROUND: We hypothesized that the benefit from ramipril on cardiac events and on left ventricular end-systolic volume (ESVI) in the Angiotensin-converting enzyme inhibition Post-revascularization Study (APRES) randomized controlled trial (RCT) was associated with long-term improvement. METHODS: For the 3.2 years after the end of the RCT, we obtained information from a national database regarding date and cause of death and hospitalization for the 159 enrolled patients. RESULTS: Assignment to ramipril in the RCT resulted in a lower rate of cardiac death or hospitalization with heart failure up to the time of complete follow-up of all patients at 4.3 years (relative risk [RR], 0.28; P =.018) and up to 1.5 years after the end of the RCT (RR, 0.35; P =.042) but not up to the complete extended follow-up time at 6.9 years (RR, 0.65; P =.27). Independent predictors for risk of future cardiac death or hospitalization with heart failure were (a) left ventricular dilation (LVD) (RR, 2.84; P =.031), defined as an increase in ESVI greater than the reproducibility coefficient, and (b) composite event of acute myocardial infarction or development of heart failure or LVD (RR, 12.44; P <.001). Ramipril significantly reduced events (a) (P =.046) and (b) (P =.015) during the RCT. CONCLUSIONS: There is congruence between the beneficial effect of ramipril on LVD, acute myocardial infarction, or heart failure and the prognostic importance of these factors and on cardiac death and hospitalization with heart failure. This observation supports and reinforces conclusions from previous APRES reports that ramipril benefits non-high-risk patients after revascularization.

Analysis of Variance↗
PubMed2005

Proinflammatory cytokines and metalloproteases are expressed in the subacromial bursa in patients with rotator cuff disease.

PURPOSE: The pathophysiology of subacromial impingement syndrome is poorly understood. We investigated the expression of inflammatory cytokines, metalloproteases, and the cyclooxygenases in the subacromial bursa in control patients and in patients with rotator cuff tear. TYPE OF STUDY: Basic science evaluation. METHODS: Eighteen patients undergoing shoulder surgery had a subacromial bursa biopsy examination. Patients were divided into 2 groups. Group I (study group) had 10 patients with a full-thickness rotator cuff tear (RCT). Group II (control group) had 8 patients. Seven of 8 underwent shoulder arthroscopy with anterior capsular reconstruction for instability; 1 of 8 underwent open reduction internal fixation for acute proximal humerus fracture. None of the patients in group II had any history of symptoms or signs consistent with subacromial impingement. H&E and immunohistochemical antibody (MMP-1, MMP-9, IL-1, IL-6, TNF-alpha, COX-1, and COX-2) stained specimens were examined by 2 blinded observers using a histologic scale (grade 0 = no staining to grade 4 = intense staining). RESULTS: Histologic evidence of inflammation was present in all patients with RCT (group I). No or mild inflammation was noted in group II. The average staining grade for inflammatory cytokines (IL-1, IL-6, TNF-alpha) and proteinases (MMP-1 and MMP-9) was significantly more pronounced in the RCT group (P < .001). Cyclooxygenase enzymes (COX-1 and COX-2) were also increased in group II (P < .001). CONCLUSIONS: A high level of expression of inflammatory cytokines, proteinases, and cyclooxygenase enzymes, known to produce a catabolic environment, is present in the subacromial bursa of patients with rotator cuff tear. CLINICAL RELEVANCE: These findings support the role of nonsteroidal anti-inflammatory drugs and corticosteroids in RCT treatment, and emphasize the importance of subacromial bursectomy to reduce inflammation in RCT surgery.

Adrenal Cortex Hormones↗
PubMed2005

Direct evidence in vivo of impaired macrophage-specific reverse cholesterol transport in ATP-binding cassette transporter A1-deficient mice.

The ATP-binding cassette transporter A1 (ABCA1) is a key regulator of high-density lipoprotein (HDL) metabolism. There is strong evidence that ABCA1 is a key regulator of reverse cholesterol transport (RCT). However, this could not be proved in vivo since hepatobiliary cholesterol transport was unchanged in ABCA1-deficient mice (ABCA1-/-). We used ABCA1-/- mice to test the hypothesis that ABCA1 is a critical determinant of macrophage-specific RCT. Although this cell-specific RCT only accounts for a tiny part of total RCT, it is widely accepted that it may have a major impact on atherosclerosis susceptibility. [(3)H]cholesterol-labeled endogenous macrophages were injected intraperitoneally into wild-type ABCA1+/+, ABCA1+/- and ABCA1-/- mice maintained on a chow diet. A direct relationship was observed between ABCA1 gene dose and plasma [(3)H]cholesterol at 24 and 48 h after the injection of tracer into the mice. Forty-eight hours after this injection, ABCA1-/- mice had significantly reduced [(3)H]cholesterol in liver (2.8-fold), small intestine enterocytes (1.7-fold) and feces (2-fold). To our knowledge, this is the first direct in vivo quantitative evidence that ABCA1 is a critical determinant of macrophage-specific RCT.

ATP Binding Cassette Transporter 1↗