Evaluation of 'implications for research' statements in systematic reviews of interventions in advanced cancer patients - a meta-research study.

BACKGROUND: Implications for research (IfR) sections are an important part of systematic reviews (SRs) to inform health care researchers and policy makers. PRISMA 2020 recommends reporting IfR, while Cochrane Reviews require a separate chapter on IfR. However, it is unclear to what extent SRs discuss IfR. We aimed i) to assess whether SRs include an IfR statement and ii) to evaluate which elements informed IfR statements. METHODS: We conducted a meta-research study based on SRs of interventions in advanced cancer patients from a previous project (CRD42019134904). As suggested in the Cochrane Handbook, we assessed if the following predefined variables were referred to in IfR statements: patient, intervention, control, outcome (PICO) and study design; concepts underlying Grading of Recommendations, Assessment, Development and Evaluation (GRADE) domains: risk of bias, inconsistency, indirectness, imprecision, publication bias. Data were independently extracted by three reviewers after piloting the data extraction form. Discrepancies were resolved in weekly in-depth discussions. RESULTS: We included 261 SRs. The majority evaluated a pharmacological intervention (n = 244, 93.5%); twenty-nine were Cochrane Reviews (11.1%). Four out of five SRs included an IfR statement (n = 210, 80.5%). IfR statements commonly addressed 'intervention' (n = 121, 57.6%), 'patient ' (n = 113, 53.8%), and 'study design' (n = 107, 51.0%). The most frequent PICO and study design combinations were 'patient and intervention ' (n = 71, 33.8%) and 'patient, intervention and study design ' (n = 34, 16.2%). Concepts underlying GRADE domains were rarely used for informing IfR recommendations: 'risk of bias ' (n = 2, 1.0%), and 'imprecision ' (n = 1, 0.5%), 'inconsistency ' (n = 1, 0.5%). Additional elements informing IfR were considerations on cost effectiveness (n = 9, 4.3%), reporting standards (n = 4, 1.9%), and individual patient data meta-analysis (n = 4, 1.9%). CONCLUSION: Although about 80% of SRs included an IfR statement, the reporting of PICO elements varied across SRs. Concepts underlying GRADE domains were rarely used to derive IfR. Further work needs to assess the generalizability beyond SRs in advanced cancer patients. We suggest that more specific guidance on which and how IfR elements to report in SRs of interventions needs to be developed. Utilizing PICO elements and concepts underlying GRADE according to the Cochrane Handbook to state IfR seems to be a reasonable approach in the interim. REGISTRATION: CRD42019134904.

Costs of cloud computing for a biometry department. A case study.

BACKGROUND: "Cloud" computing providers, such as the Amazon Web Services (AWS), offer stable and scalable computational resources based on hardware virtualization, with short, usually hourly, billing periods. The idea of pay-as-you-use seems appealing for biometry research units which have only limited access to university or corporate data center resources or grids. OBJECTIVES: This case study compares the costs of an existing heterogeneous on-site hardware pool in a Medical Biometry and Statistics department to a comparable AWS offer. METHODS: The "total cost of ownership", including all direct costs, is determined for the on-site hardware, and hourly prices are derived, based on actual system utilization during the year 2011. Indirect costs, which are difficult to quantify are not included in this comparison, but nevertheless some rough guidance from our experience is given. To indicate the scale of costs for a methodological research project, a simulation study of a permutation-based statistical approach is performed using AWS and on-site hardware. RESULTS: In the presented case, with a system utilization of 25-30 percent and 3-5-year amortization, on-site hardware can result in smaller costs, compared to hourly rental in the cloud dependent on the instance chosen. Renting cloud instances with sufficient main memory is a deciding factor in this comparison. CONCLUSIONS: Costs for on-site hardware may vary, depending on the specific infrastructure at a research unit, but have only moderate impact on the overall comparison and subsequent decision for obtaining affordable scientific computing resources. Overall utilization has a much stronger impact as it determines the actual computing hours needed per year. Taking this into ac count, cloud computing might still be a viable option for projects with limited maturity, or as a supplement for short peaks in demand.

Pancreaticoduodenectomy (classic Whipple) versus pylorus-preserving pancreaticoduodenectomy (pp Whipple) for surgical treatment of periampullary and pancreatic carcinoma.

BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer death for men and the fifth for women. The standard treatment for resectable tumours is either a classic Whipple operation or a pylorus-preserving pancreaticoduodenectomy but it is still unclear which of the two procedures is more favourable in terms of survival, mortality, complications, perioperative factors and quality of life. OBJECTIVES: Several publications pointed out both advantages and disadvantages of both techniques and the current basis of evidence remains unclear. The objective of this systematic review is to compare the effectiveness of each technique. SEARCH STRATEGY: A search was conducted to identify all published and unpublished randomised controlled trials. Trials were identified by searching the following electronic databases - The Cochrane Library, MEDLINE, EMBASE and Current Contents. Reference lists from trials selected by electronic searching were hand-searched to identify further relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the classical Whipple (CW) with the pylorus-preserving pancreaticoduodenectomy (PPW) were considered eligible if patients with periampullary or pancreatic carcinoma were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data for included studies. A random-effects model was used for pooling data from the different trials. Binary outcomes were compared using odds ratios, continuous outcomes were pooled using weighted mean differences and hazard ratios were used to for the meta-analysis of survival data. The methodological quality of included studies was evaluated independently by two authors according to quality standards and by using a questionnaire that covers different aspects of quality. MAIN RESULTS: 1235 abstracts were retrieved and checked for eligibility and seven RCTs were finally included. The critical appraisal revealed vast heterogeneity with respect to methodological quality and outcome parameters. The comparison of overall in-hospital mortality (odds ratio 0.49; 95% CI 0.17 to 1.40; P=0.18), overall survival (hazard ratio 0.84; 95% CI 0.61 to 1.16; P=0.29) and morbidity showed no significant difference. However, operating time (weighted mean difference -68.26 min; 95% CI -105.70 to -30.83; P=0.0004) and intra-operative blood loss (weighted mean difference -0.76 ml; 95% CI -0.96 to -0.56; P<0.00001) were significantly reduced in the PPW group. AUTHORS' CONCLUSIONS: There is no evidence of relevant differences in mortality, morbidity and survival between the PPW and the CW. Given obvious clinical and methodological inter-study heterogeneity, future efforts have to be undertaken to perform high quality RCTs of complex surgical interventions on the basis of well defined outcome parameters.

High-dose chemotherapy with autologous stem cell transplantation in the first line treatment of aggressive non-Hodgkin lymphoma (NHL) in adults.

BACKGROUND: High-dose chemotherapy with autologous stem cell support (HDT) has been proven effective in relapsed aggressive non-Hodgkin lymphoma (NHL). However, conflicting results of HDT as part of first-line treatment have been reported in randomised controlled trials (RCTs). We undertook a systematic review and meta-analysis to assess the effects of such treatment. OBJECTIVES: To determine whether high-dose chemotherapy with autologous stem cell transplantation as part of first-line treatment improves survival in patients with aggressive non-Hodgkin lymphoma. SEARCH STRATEGY: MEDLINE, EMBASE, Cancer Lit, the Cochrane Library and smaller databases, Internet-databases of ongoing trials, conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology were searched. We included full-text, abstract publications and unpublished data. SELECTION CRITERIA: Randomised controlled trials comparing conventional chemotherapy versus high-dose chemotherapy in the first-line treatment of adults with aggressive non-Hodgkin lymphoma were included in this review. DATA COLLECTION AND ANALYSIS: Eligibility and quality assessment, data extraction and analysis were done in duplicate. All authors were contacted to obtain missing data and asked to provide individual patient data. MAIN RESULTS: Fifteen RCTs including 3079 patients were eligible for this meta-analysis. Overall treatment-related mortality was 6.0% in the HDT group and not significantly different compared to conventional chemotherapy (OR 1.33 [95% CI 0.91 to 1.93], P=0.14). 13 studies including 2018 patients showed significantly higher CR rates in the group receiving HDT (OR 1.32, [95% CI 1.09 to 1.59], P=0.004). However, HDT did not have an effect on OS, when compared to conventional chemotherapy. The pooled HR was 1.04 ([95% CI 0.91 to 1.18], P=0.58). There was no statistical heterogeneity among the trials. Sensitivity analyses underlined the robustness of these results. Subgroup analysis of prognostic groups according to IPI did not show any survival difference between HDT and controls in 12 trials (low and low-intermediate risk IPI: HR 1.41[95% CI 0.95 to 2.10], P=0.09; high-intermediate and high risk IPI: HR 0.97 [95% CI 0.83 to 1.13], P=0.71. Event-free survival (EFS) also showed no significant difference between HDT and CT (HR 0.93, [95% CI 0.81 to 1.07], P=0.31). Other possible risk factors such as the proportion of patient with diffuse large cell lymphoma, protocol adherence, HDT strategy, response status before HDT, conditioning regimens and methodological issues were analysed in sensitivity analyses. However, there was no evidence for an association between these factors and the results of our analyses. AUTHORS' CONCLUSIONS: . Despite higher CR rates, there is no benefit for high-dose chemotherapy with stem cell transplantation as a first line treatment in patients with aggressive NHL.

Chemotherapy plus Rituximab versus chemotherapy alone for B-cell non-Hodgkin's lymphoma.

BACKGROUND: Rituximab has been shown to improve response rates and progression free survival when added to chemotherapy in patients with indolent and mantle cell lymphoma. However, the impact of R on overall survival (OS) when given in combination with chemotherapy (R-chemo) has remained unclear so far. OBJECTIVES: We thus performed a comprehensive systematic review in this group of patients to compare R-chemo with chemotherapy alone with respect to OS. Other endpoints were overall response rate (ORR), toxicity and disease control as assessed by measures such as time to treatment failure (TTF), event free-survival (EFS), progression free-survival (PFS) and time to progression (TTP). SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE and conference proceeding from 1990 to 2005. SELECTION CRITERIA: Only randomised controlled trials (RCT) comparing R-chemo with chemotherapy alone in patients with newly diagnosed or relapsed indolent lymphoma and mantle cell lymphoma (MCL) were included. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed the study quality. Number needed to treat (NNT) were calculated to facilitate interpretation. MAIN RESULTS: Seven randomised controlled trials involving 1943 patients with follicular lymphoma, mantle cell lymphoma, or other indolent lymphomas were included in the meta-analysis. Five studies were published as full-text articles, and two were in abstract form. Patients treated with R-chemo had better overall survival (hazard ratio [HR] for mortality 0.65; 95% confidence interval (CI) 0.54 to 0.78), overall response (relative risk of tumour response 1.21; 95% CI 1.16 to 1.27), and disease control (HR of disease event 0.62; 95% CI 0.55 to 0.71) than patients treated with chemotherapy alone. R-chemo improved overall survival in patients with follicular lymphoma (HR for mortality 0.63; 95% CI 0.51 to 0.79) and in patients with mantle cell lymphoma (HR for mortality 0.60; 95% CI 0.37 to 0.98). However, in the latter case, there was heterogeneity among the trials (P 0.07), making the survival benefit less reliable. AUTHORS' CONCLUSIONS: The systematic review demonstrated improved OS for patients with indolent lymphoma, particularly in the subgroups of follicular and in mantle cell lymphoma when treated with R-chemo compared to chemotherapy alone.

Erythropoietin or darbepoetin for patients with cancer.

BACKGROUND: Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (Epo), darbepoetin (Darbepo) and red blood cell transfusions. OBJECTIVES: The aim of this systematic review was to assess the effects of Epo or Darbepo to either prevent or treat anaemia in cancer patients. SEARCH STRATEGY: We searched the Central Register of Controlled Trials, MEDLINE and EMBASE and other data bases. Searches were done for the periods 01/1985 to 12/2001 for the first review and 1/2002 to 04/2005 for the update. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials on managing anaemia in cancer patients that compared the use of Epo/Darbepo (plus transfusion if needed) with observation until red blood cell transfusion was required. DATA COLLECTION AND ANALYSIS: Several reviewers independently assessed trial quality and extracted data. MAIN RESULTS: This update of the systematic review included a total of 57 trials with 9,353 patients. Of these, 27 trials with 3,287 adults were also included in the first Cochrane Review. Thirty trials with 6,066 patients were added during the update process. Use of Epo/Darbepo significantly reduced the relative risk of red blood cell transfusions (RR 0.64; 95% CI 0.60 to 0.68, 42 trials, n = 6,510). On average participants in the Epo/Darbepo group received one unit of blood less than the control group (WMD -1.05; 95% CI -1.32 to -0.78, 14 trials, n = 2,353). For participants with baseline haemoglobin below 12 g/dL haematological response was observed more often in participants receiving Epo/Darbepo (RR 3.43; 95% CI 3.07 to 3.84, 22 trials, n = 4,307). There was suggestive evidence that Epo/Darbepo may improve Quality of Life (QoL). The relative risk for thrombo embolic complications was increased in patients receiving Epo/Darbepo compared to controls (RR 1.67, 95% CI 1.35 to 2.06; 35 trials, n = 6,769). Uncertainties remain whether and how Epo/Darbepo effects tumour response (fixed effect RR 1.12; 95% CI 1.01 to 1.23, 13 trials, n = 2,833; random effects: RR 1.09; 95% CI 0.94 to 1.26) or overall survival (unadjusted and adjusted data: HR 1.08; 95% CI 0.99 to 1.18; 42 trials, n = 8,167). AUTHORS' CONCLUSIONS: There is consistent evidence that administration of Epo/Darbepo reduces the relative risk for blood transfusions and the number of units transfused in cancer patients. For patients with baseline haemoglobin below 12 g/dL (mild anaemia) there is strong evidence that Epo/Darbepo improves haematological response. There is suggestive evidence that Epo/Darbepo may improve QoL. However, there is strong evidence that Epo/Darbepo increases the relative risk for thrombo embolic complications. Whether and how Epo/Darbepo effects tumour response and overall survival remains uncertain.

Purine antagonists for chronic lymphocytic leukaemia.

BACKGROUND: Recent trials suggest improved response rates for purine antagonists compared to alkylator-based regimens in the treatment of B-CLL. However, none was able to show a survival advantage. OBJECTIVES: To determine if there is any advantage of purine antagonists compared to alkylating agents (alone or in combination) in the treatment of patients with previously untreated B-CLL. SEARCH STRATEGY: Medical databases (Cochrane Library, MEDLINE, EMBASE), conference proceedings and internet-based trial registers were searched electronically and/or by hand (1990-2003). All references were checked for further trial information. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials comparing purine antagonists as single agents with alkylator-based regimens in patients with previously untreated B-CLL were included. We included full-text and abstract publications as well as unpublished data. DATA COLLECTION AND ANALYSIS: Data extraction and quality assessment were done in duplicate by two independent reviewers. Missing data were obtained from original authors. Endpoints included overall survival, overall response rate, rate of complete remissions, progression-free survival, treatment-related morbidity and mortality. MAIN RESULTS: Five trials with 1838 randomised patients were included. There is some evidence for improved overall survival after treatment with purine antagonists compared to alkylators, but statistical significance was not reached (HR 0.89 [95% CI 0.78-1.01], 4 trials, n=1638). However, the relative risk for achieving an overall response (RR 1.22 [95% CI 1.13-1.31], 5 trials, n=1751) and complete remission (RR 1.94 [95% CI 1.65-2.28], 5 trials, n=1751) was significantly higher, resulting in a longer progression-free survival (HR 0.70 [95% CI 0.61-0.82], 4 trials, n=1638). Incidence of grade III/IV infections was significantly higher in patients receiving treatment with purine antagonists (RR 1.83 [95% 1.30-2.58], 4 trials, n=1620). There was no significant difference concerning the relative risk for grade III/IV neutropenia (RR 1.14 [95% CI 0.98-1.34], 4 trials, n=1620) and therapy-related mortality (RR 0.94 [95% CI 0.45-1.95]). Overall incidence of hemolytic anemia was low, but significantly increased in the purine antagonist group (RR 3.36 [95% CI 1.27-8.91], 3 trials, n=1258). AUTHORS' CONCLUSIONS: Despite significantly increased overall response and complete remission rates and longer progression-free survival with first-line treatment of B-CLL patients with single-agent purine antagonists, we were not able to detect a statistically significant improvement of overall survival compared to alkylator-based regimens. Furthermore, the use of purine antagonists also augments the risk for grade III/IV infections and hemolytic anemia.

Application of fuzzy inference to European patients to predict cervical lymph node metastasis in carcinoma of the tongue.

In head and neck cancers, the presence of cervical lymph node metastasis is an important determinant of outcome. Many attempts have been made to predict cervical lymph node metastasis, but the accuracy of currently available techniques remains inadequate. We used fuzzy inference to predict cervical lymph node metastasis retrospectively in 75 patients with squamous cell carcinoma of the tongue and prospectively in 23 patients. Our model was based on three variables: tumor size, keratinization, and mode of invasion. The accuracy of fuzzy inference for the prediction of cervical lymph node metastasis in the 75 patients studied retrospectively was 86.7%, the sensitivity was 70.8%, and the specificity was 94.1%. In the 23 patients studied prospectively, the accuracy was 91.3%, the sensitivity was 50.0%, and the specificity was 95.2%. The accuracy obtained in this European series of patients was similar to that previously obtained in Japanese patients. We conclude that fuzzy inference may be a useful method for predicting cervical lymph node metastasis. Its high specificity is likely to reduce the number of unnecessary neck dissections. However, the current level sensitivity is inadequate for routine clinical use. Therefore, other predictors of lymph node metastasis should be identified to refine the current model.

Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma.

BACKGROUND: Granulopoiesis-stimulating factors, such as granulocyte-colony-stimulating factor (G-CSF) and granulocyte-macrophage-colony-stimulating factor (GM-CSF), are being used to prevent febrile neutropenia and infection in patients undergoing treatment for malignant lymphoma. The question of whether G-CSF and GM-CSF improve dose intensity, tumour response, and overall survival in this patient population has not been answered yet. Since the results from single studies are inconclusive, a systematic review was undertaken. OBJECTIVES: To determine the effectiveness of G-CSF and GM-CSF in patients with malignant lymphoma with respect to preventing neutropenia, febrile neutropenia and infection; improving quality of life, adherence to treatment protocol, tumour response, freedom from treatment failure (FFTF) and overall survival (OS); and adverse effects. SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE, CancerLit, and other relevant literature databases; internet databases of ongoing trials; and conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology (1980 - 2003). We included full-text and abstract publications as well as unpublished data. SELECTION CRITERIA: Randomised controlled trials comparing prophylaxis with G-CSF or GM-CSF versus placebo/no prophylaxis in adult patients with malignant lymphoma undergoing chemotherapy were included for review. Both study arms had to receive identical chemotherapy and supportive care. DATA COLLECTION AND ANALYSIS: Trial eligibility and quality assessment, data extraction and analysis were done in duplicate. Authors were contacted to obtain missing data. MAIN RESULTS: We included 12 eligible randomised controlled trials with 1823 patients. Compared with no prophylaxis, both G-CSF and GM-CSF significantly reduced the relative risk (RR) for severe neutropenia (RR 0.67; 95% confidence interval (CI) 0.60 to 0.73), febrile neutropenia (RR 0.74; 95% CI 0.62 to 0.89) and infection (RR 0.74; 95% CI 0.64 to 0.85). There was no evidence that either G-CSF or GM-CSF reduced the number of patients requiring intravenous antibiotics (RR 0.82; 95%CI 0.57 to 1.18); lowered infection related mortality (RR 1.37; 95% CI 0.66 to 2.82); or improved complete tumour response (RR 1.02; 95% CI 0.94 to 1.11), FFTF (hazard ratio 1.11; 95% CI 0.91 to 1.35) and OS (hazard ratio 1.00; 95% CI 0.86 to 1.16). One study evaluated quality of life parameters and found no differences between the treatment groups. REVIEWERS' CONCLUSIONS: G-CSF and GM-CSF, when used as a prophylaxis in patients with malignant lymphoma undergoing conventional chemotherapy, reduce the risk of neutropenia, febrile neutropenia and infection. However, based on the randomised trials currently available, there is no evidence that either G-CSF or GM-CSF provide a significant advantage in terms of complete tumour response, FFTF or OS.

Erythropoietin for patients with malignant disease.

BACKGROUND: Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (EPO) and red blood cell transfusions. OBJECTIVES: The aim of this systematic review was to assess the effect of erythropoietin to either prevent or treat anaemia in cancer patients. SEARCH STRATEGY: We searched the Central Register of Controlled Trials, MEDLINE (01/1985 to 12/2001), EMBASE (01/1985 to 12/2001), other databases and reference lists of articles. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials comparing the use of recombinant human erythropoietin (plus transfusion if needed) with red blood cell transfusions alone for the treatment or prevention of anaemia in cancer patients. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. All authors from included studies were contacted for additional information. MAIN RESULTS: Twenty seven trials with 3,287 adults were included. Use of erythropoietin significantly reduced the relative risk of red blood cell transfusions (RR 0.67; 95% CI 0.62 to 0.73, 25 trials, n = 3,069). On average participants in the erythropoietin group received one unit of blood less than the control group (WMD -1.00; 95% CI-1.31 to -0.70, 13 trials, n = 2,056). For participants with baseline haemoglobin below 10 g/dL haematological response was observed more often in participants receiving EPO (RR 3.60; 95% CI 3.07 to 4.23, 14 trials, n = 2,347). There was inconclusive evidence whether EPO improves tumour response (fixed effect RR 1.36; 95% CI 1.07 to 1.72, seven trials, n = 1,150; random effects: RR 1.21; 95% CI 0.92 to 1.59) and overall survival (adjusted data: HR 0.81; 95% CI 0.67 to 0.99; unadjusted data: HR 0.84; 95% CI 0.69 to 1.02, 19 trials, n = 2,865). There were no statistically significant adverse effects. Evidence was inconclusive with respect to quality of life and fatigue. REVIEWERS' CONCLUSIONS: There is consistent evidence that the administration of erythropoietin reduces the risk for blood transfusions and the number of units transfused in cancer patients. For patients with baseline haemoglobin below 10 g/dL there is strong evidence that erythropoietin improves haematological response. There is inconclusive evidence whether erythropoietin improves tumour response and overall survival. Research on side effects is inconclusive.

Ketotifen alone or as additional medication for long-term control of asthma and wheeze in children.

BACKGROUND: Ketotifen is an antihistamine which may be used to treat asthma. Since administering inhaled therapy to younger children can be difficult, an oral agent such as ketotifen offers potential advantages. OBJECTIVES: The objective of this review is to determine, whether ketotifen alone or in combination with other co-interventions results in better control of asthma in children with asthma and/or wheezing and examine its safety profile. SEARCH STRATEGY: We searched the Cochrane Airways Group register of trials (based on MEDLINE, EMBASE, CINAHL and handsearched respiratory journals) and reference lists of articles. The latest search was carried out in October 2002. SELECTION CRITERIA: Clinical studies had to be randomised-controlled and double-blinded, comparing oral ketotifen with placebo in children with asthma and/or wheeze for at least eight weeks at a dose not less than one mg daily. DATA COLLECTION AND ANALYSIS: Two reviewers independently performed selection of trials, quality assessment and data extraction; a third reviewer was included in the consensus process if necessary. MAIN RESULTS: A total of 26 relevant studies involving 1826 participants were included in this review. Children's age ranged from 4 months to 18 years and ketotifen was given between 10 and 32 weeks. The proportion of children able to reduce or stop their bronchodilator use within 12 to 16 weeks of treatment was significantly higher in the ketotifen group (relative risk 2.39, 95% CI 1.64 to 3.48) based on four trials; this result was statistically significant in a subgroup of two trials with well described and adequate method of blinding. Statistically significant beneficial effects of ketotifen were also observed in the following secondary outcomes: efficacy evaluated by physician (10 trials) and parents/patients (7 trials), asthma symptom score (4 trials), asthma exacerbations (2 trials), and reduction in use of oral steroids (4 trials). However, sub-group analyses of trials with well described and adequate method of blinding was only significant for the outcome asthma symptom score and non-significant for the remaining secondary outcomes. Reported side effects were more frequent in the ketotifen group (sedation: 21%, weight gain: 27%) than in the placebo group (sedation: 12%, weight gain: 17%). REVIEWER'S CONCLUSIONS: Evidence from randomised controlled trials indicates that ketotifen alone or in combination with other co-interventions improves control of asthma and wheezing in children with mild and moderate asthma. However due to the high proportion of children with atopy in some trials the results cannot necessarily be generalised to all asthmatic children. The benefit is obtained at the cost of minor side effects, namely sedation and weight gain. The validity of this conclusion is limited by the low reported, methodological quality of included trials.

Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma.

BACKGROUND: Granulopoiesis-stimulating factors (G-CSF and GM-CSF) are being used to prevent febrile neutropenia and infections in the treatment of patients with malignant lymphoma. The question whether G-CSF and GM-CSF improve dose-intensity, tumour response and overall survival in this patient population has not been answered yet. Since the results from single studies are inconclusive a systematic review was required. OBJECTIVES: To undertake a systematic review in patients with malignant lymphoma to determine the effectiveness of G-CSF and GM-CSF to prevent neutropenia, febrile neutropenia, infection, improve quality of life, adherence to the treatment protocol, tumour response, freedom from treatment failure (FFTF), overall survival (OS) and to assess adverse events of G-CSF and GM-CSF. SEARCH STRATEGY: Medline, Embase, CancerLit, the Cochrane Library and smaller databases, Internet-databases of ongoing trials, conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology were searched. We included full-text and abstract publications as well as unpublished data. SELECTION CRITERIA: Randomised controlled trials comparing prophylaxis with G-CSF or GM-CSF versus placebo/no prophylaxis in adult patients with malignant lymphoma undergoing chemotherapy were included in this review. Both study arms had to receive identical chemotherapy and supportive care. DATA COLLECTION AND ANALYSIS: Eligibility and quality assessment, data extraction and analysis were done in duplicate. Authors were contacted to obtain missing data. MAIN RESULTS: We included 12 eligible studies with 1.823 randomised patients. Compared with no prophylaxis, G-/GM-CSF significantly reduced the relative risk for severe neutropenia (RR 0.67 [95% CI 0.60-0.73]), febrile neutropenia (RR 0.74 [95% CI 0.62-0.89]) and infection (RR 0.74 [95% CI 0.64-0.85]). There was no evidence for G-/GM-CSF to decrease the number of patients who required iv antibiotics (RR 0.82 [95%CI 0.57-1.18]), to reduce infection related mortality (RR 1.37 [95% CI 0.66-2.82]), or to improve complete tumour response (RR 1.02 [95% CI 0.94-1.11]), FFTF (HR 1.11 [95% CI 0.91-1.35]) and OS (HR 1.00 [95% CI 0.86-1.16]). One study evaluated quality of life parameters and did not find differences between the groups. REVIEWER'S CONCLUSIONS: G-CSF and GM-CSF, when given prophylactically in patients with malignant lymphoma undergoing conventional chemotherapy, reduce the risk of neutropenia, febrile neutropenia and infection. However, based on the currently available randomised trials in this clinical setting, there is no evidence for G-/GM-CSF to provide a significant advantage in terms of complete tumour response, FFTF and OS.

Comparison of fuzzy inference, logistic regression, and classification trees (CART). Prediction of cervical lymph node metastasis in carcinoma of the tongue.

OBJECTIVES: In this paper three statistical methods [logistic regression, classification and regression tree (CART), and fuzzy inference] for the prediction of lymph node metastasis in carcinoma of the tongue are compared. METHODS: A retrospective collection of data in 75 patients treated for tongue cancer was carried out at the Clinic and Policlinic for Oral and Maxillo-facial Surgery at the University Hospital of Freiburg in Germany between January 1990 and December 1999; biopsy material was used for laboratory evaluations. Statistical methods for the prediction of lymph node metastasis were compared using ROC curves and accuracy rates. RESULTS: All three methods show similar results for the prediction of lymph node metastasis with slightly superior results for fuzzy inference and CART. A great overlap is apparent in the ROC curves. The best result observed for fuzzy inference and CART was a sensitivity of 79.2% [95% confidence interval: (57.8%; 92.9%)] and a specificity of 86.3% (73.7%; 94.3%); the best result for predictions based on the logistic regression was a sensitivity of 66.7% (44.7%; 84.4%) and a specificity of 80.4% (66.9%; 90.2%). Accuracy rates of fuzzy method and CART were higher [accuracy rate for fuzzy method and CART: 84% (73.7%; 91.4%), for logistic regression method: 73.3%, 95%-CI: (61.9%; 82.9%)]. CONCLUSIONS: From a clinical point of view, the predictive ability of the three methods is not sufficiently large to justify use of these methods in daily practice. Other factors probably on the molecular level are needed for the prediction of lymph node metastasis.

Shutting down operating theater ventilation when the theater is not in use: infection control and environmental aspects.

OBJECTIVE: In hospital operating rooms (ORs), specially conditioned air is supplied to protect patients from airborne agents that may cause infections. This study investigated whether it is hygienically safe to shut down the air supply at night if measures are taken to ensure a timely restart before surgery is performed. DESIGN: Experimental study. SETTING: Neurosurgical OR of a German university hospital. METHODS: The ventilation system was switched off and restarted after 10 hours. Particles suspended in the air near the operating table were counted, OR temperature was measured, and settle plates were exposed and incubated. RESULTS: In 13 investigations, a median of 1.3 x 10(4) particles 0.5 microm/m3 or greater (range, 5.8 x 10(3) to 1.1 x 10(5)) were documented immediately after restart in the morning. After 10 minutes and subsequently, no test showed a particle count exceeding the threshold limit of 1.0 x 10(4) particles 0.5 microm/m3 or greater recommended by the German Society of Hygiene and Microbiology. Only a few colony-forming units (CFU) were detected per settle plate (median, 0 CFU/60 cm2; range, 0 to 8) and OR temperatures quickly reached normal levels. CONCLUSIONS: Shutting down OR ventilation during off-duty periods does not appear to result in an unacceptably high particle count or microbial contamination of the OR air shortly after the system is restarted. Because substantial energy and cost savings are likely, this should be considered in hygienically safe heating, ventilation, and air conditioning systems. However, normal ventilation should be established at least 30 minutes before surgical activity.

Ursodeoxycholic acid and/or antibiotics for prevention of biliary stent occlusion.

BACKGROUND: Malignant biliary obstruction, which requires endoscopic stenting as palliative therapy, is often complicated by clogging of the stent with subsequent jaundice and/or cholangitis. Stent clogging may be caused by microbiological adhesion and biliary stasis. Therefore, antibiotics and choleretic agents like ursodeoxycholic acid (UDCA) have been investigated to see whether they prolong stent patency. OBJECTIVES: To evaluate if UDCA and/or antibiotics may prolong stent patency and survival in patients with strictures of the biliary tract and endoscopically inserted stents. SEARCH STRATEGY: The Trials Register of The Cochrane Hepato-Biliary Group, The Cochrane Library, MEDLINE, Current Contents, EMBASE, and CancerLit were searched until June 2001. Reference lists of the identified articles were checked for further trials. SELECTION CRITERIA: All randomised or quasi-randomised clinical trials investigating UDCA and/or antibiotics in patients with biliary stents were considered for inclusion, regardless of blinding, language, and publication status. DATA COLLECTION AND ANALYSIS: Trial inclusion, quality assessment, and data extraction were performed independently by two reviewers. Principal investigators were contacted for further information. Survival data were combined by using hazard ratios (with 95% confidence interval (95% CI)). MAIN RESULTS: Five non-blinded randomised trials with 258 patients with malignant strictures treated with polyethylene stents were included. Three trials, including 152 patients, investigated a combination of UDCA and antibiotics versus no treatment. The meta-analysis of these three trials does not show a significant treatment effect on the duration of stent patency (hazard ratio (random effects model) 0.58, 95% CI 0.22 to 1.54) or mortality (hazard ratio (fixed effect model) 0.99, 95% CI 0.68 to 1.43). Two trials with 106 patients compared antibiotics with no treatment, one of these trials used a combination of antibiotics and rowachol (an 'alternative' drug of the 'mint' family). The pooled results of these two trials do not show significant effects of antibiotics on the duration of stent patency (hazard ratio (fixed effect model) 0.69 (95% CI 0.37 to 1.30)) or mortality (hazard ratio (fixed effect model) 1.23 (95% CI 0.72 to 2.08). Data concerning duration of hospital stay, frequency of cholangitis, and rate of infectious complications due to selection of antibiotic resistant bacteria strains were not available. REVIEWER'S CONCLUSIONS: Treatment with UDCA and/or antibiotics to prevent clogging of biliary stents in patients with malignant stricture of the biliary tract cannot be recommended routinely on the basis of the existing randomised clinical trials. Further trials are needed with rigorous methodology and sufficient statistical power.

Granulopoiesis-stimulating factors in the prevention for adverse effects in the therapeutic treatment of malignant lymphoma.

BACKGROUND: Granulopoiesis-stimulating factors (G-CSF and GM-CSF) are being used to prevent febrile neutropenia and infections in the treatment of patients with malignant lymphoma. The question whether G-CSF and GM-CSF improve dose-intensity, tumour response and overall survival in this patient population has not been answered yet. Since the results from single studies are inconclusive a systematic review was required. OBJECTIVES: To undertake a systematic review in patients with malignant lymphoma to determine the effectiveness of G-CSF and GM-CSF to prevent neutropenia, febrile neutropenia, infection, improve quality of life, adherence to the treatment protocol, tumour response, freedom from treatment failure (FFTF), overall survival (OS) and to assess adverse events of G-CSF and GM-CSF. SEARCH STRATEGY: Medline, Embase, CancerLit, the Cochrane Library and smaller databases, Internet-databases of ongoing trials, conference proceedings of the American Society of Clinical Oncology and the American Society of Hematology were searched. We included full-text and abstract publications as well as unpublished data. SELECTION CRITERIA: Randomised controlled trials comparing prophylaxis with G-CSF or GM-CSF versus placebo/no prophylaxis in adult patients with malignant lymphoma undergoing chemotherapy were included in this review. Both study arms had to receive identical chemotherapy and supportive care. DATA COLLECTION AND ANALYSIS: Eligibility and quality assessment, data extraction and analysis were done in duplicate. All authors were contacted to obtain missing data. MAIN RESULTS: We included 11 eligible studies with 1434 randomised patients. Compared with no prophylaxis, G-/GM-CSF significantly reduced the relative risk for severe neutropenia (RR 0.64 [95% CI 0.55-0.75]), febrile neutropenia (RR 0.74 [95% CI 0.62-0.89]) and infection (RR 0.74 [95% CI 0.64-0.85]). There was no evidence for G-/GM-CSF to decrease the number of patients who required iv antibiotics (RR 0.82 [95%CI 0.57-1.18]), to reduce infection related mortality (RR 2.07 [95% CI 0.81-5.34]), or to improve complete tumour response (RR 1.06 [95% CI 0.96-1.16]), FFTF (HR 1.22 [95% CI 0.83-1.80]) and OS (HR 0.98 [95% CI 0.81-1.18]). None of the studies evaluated quality of life parameters. REVIEWER'S CONCLUSIONS: G-CSF and GM-CSF, when given prophylactically in patients with malignant lymphoma undergoing conventional chemotherapy, reduce the risk of neutropenia, febrile neutropenia and infection. However, based on the currently available randomised trials in this clinical setting, there is no evidence for G-/GM-CSF to provide a significant advantage in terms of complete tumour response, FFTF and OS.