Probiotics-supplemented feeding in extremely low-birth-weight infants.

OBJECTIVE: The objective of this trial was to test whether probiotic-supplemented feeding to extremely low-birth-weight (ELBW) infants will improve growth as determined by decreasing the percentage of infants with weight below the 10th percentile at 34 weeks postmenstrual age (PMA). Other important outcome measures, such as improving feeding tolerance determined by tolerating larger volume of feeding per day and reducing antimicrobial treatment days during the first 28 days from the initiation of feeding supplementation were also evaluated. STUDY DESIGN: We conducted a multicenter randomized controlled double-blinded clinical study. The probiotics-supplementation (PS) group received Lactobacillus rhamnosus GG and Bifidobacterium infantis added to the first enteral feeding and continued once daily with feedings thereafter until discharge or until 34 weeks (PMA). The control (C) group received unsupplemented feedings. Infant weight and feeding volumes were recorded daily during the first 28 days of study period. Weights were also recorded at 34 weeks PMA. RESULT: A total of 101 infants were enrolled (PS 50 versus C 51). There was no difference between the two groups in the percentage of infants with weight below the 10th percentile at 34 weeks PMA (PS group 58% versus C group 60%, (P value 0.83)) or in the average volume of feeding during 28 days after study entry (PS group 59 ml kg(-1) versus C group 71 ml kg(-1), (P value 0.11)). Calculated growth velocity was higher in the PS group compared with the C group (14.9 versus 12.6 g per day, (P value 0.05)). Incidences of necrotizing enterocolitis (NEC), as well as mortality were similar between the two groups. CONCLUSION: Although probiotic-supplemented feedings improve growth velocity in ELBW infants, there was no improvement in the percentage of infants with growth delay at 34 weeks PMA. There were no probiotic-related adverse events reported.

Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data.

BACKGROUND: Many randomised controlled trials have investigated the effect of adjuvant chemotherapy in operable non-small-cell lung cancer. We undertook two comprehensive systematic reviews and meta-analyses to establish the effects of adding adjuvant chemotherapy to surgery, or to surgery plus radiotherapy. METHODS: We included randomised trials, not confounded by additional therapeutic differences between the two groups and that started randomisation on or after Jan 1, 1965, which compared surgery plus adjuvant chemotherapy versus surgery alone, or surgery plus adjuvant radiotherapy and chemotherapy versus surgery plus adjuvant radiotherapy. Updated individual patient data were collected, checked, and included in meta-analyses stratified by trial. The primary endpoint was overall survival, defined as time from randomisation until death by any cause. All analyses were by intention to treat. FINDINGS: The first meta-analysis of surgery plus chemotherapy versus surgery alone was based on 34 trial comparisons and 8447 patients (3323 deaths). We recorded a benefit of adding chemotherapy after surgery (hazard ratio [HR] 0.86, 95% CI 0.81-0.92, p<0.0001), with an absolute increase in survival of 4% (95% CI 3-6) at 5 years (from 60% to 64%). The second meta-analysis of surgery plus radiotherapy and chemotherapy versus surgery plus radiotherapy was based on 13 trial comparisons and 2660 patients (1909 deaths). We recorded a benefit of adding chemotherapy to surgery plus radiotherapy (HR 0.88, 95% CI 0.81-0.97, p=0.009), representing an absolute improvement in survival of 4% (95% CI 1-8) at 5 years (from 29% to 33%). In both meta-analyses we noted little variation in effect according to the type of chemotherapy, other trial characteristics, or patient subgroup. INTERPRETATION: The addition of adjuvant chemotherapy after surgery for patients with operable non-small-cell lung cancer improves survival, irrespective of whether chemotherapy was adjuvant to surgery alone or adjuvant to surgery plus radiotherapy. FUNDING: UK Medical Research Council, Institut Gustave-Roussy, Programme Hospitalier de Recherche Clinique (AOM 05 209), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Single photon emission from diamond nanocrystals in an opal photonic crystal.

We present the first optical measurement of a single nitrogen-vacancy (NV) center in a three-dimensional photonic crystal. The photonic crystal, fabricated by self-assembly of polystyrene microspheres, exhibits a photonic stopband that overlaps the NV photoluminescence spectrum. A modified emission spectrum and photon antibunching were measured from the NV centers. Time-resolved fluorescence measurements revealed a 30% increase in the source lifetime. Encapsulation of single NV centers in a three-dimensional photonic crystal is a step towards controlling emission properties of a single photon source.

Chemotherapy and surgery versus surgery alone in non-small cell lung cancer.

BACKGROUND: The role of pre-operative chemotherapy in the treatment of patients with non-small cell lung cancer (NSCLC) was not clear. A systematic review and quantitative meta-analysis were therefore undertaken to evaluate the available evidence from randomised trials. OBJECTIVES: To evaluate the effect of pre-operative chemotherapy on survival in patients with non-small cell lung cancer. If adequate data are available, to investigate whether or not pre-defined patient subgroups benefit more or less from pre-operative chemotherapy. SEARCH STRATEGY: MEDLINE and CANCERLIT searches for randomised controlled trials (RCTs) were supplemented by information from trial registers and by handsearching relevant meeting proceedings and by discussion with relevant trialists and organisations. SELECTION CRITERIA: RCTs were eligible for inclusion provided the patients had been randomised between chemotherapy followed by surgery versus surgery alone and that the method of randomisation precluded prior knowledge of the treatment to be assigned. DATA COLLECTION AND ANALYSIS: A systematic review and meta-analysis based on aggregate data extracted from trial publications was carried out to assess the effectiveness of pre-operative chemotherapy in NSCLC. This involved identifying eligible RCTs and extracting aggregate data from the abstracts or reports of these RCTs. Hazard ratios were calculated from published summary statistics and then combined to give pooled estimates of treatment efficacy. MAIN RESULTS: Twelve eligible RCTs were identified. Data were available from seven RCTs including 988 patients (75% of eligible patients). Pre-operative chemotherapy increased survival with a hazard ratio of 0.82 (95%CI 0.69-0.97) P = 0.022. This is equivalent to an absolute benefit of 6%, increasing overall survival across all stages of disease from 14% to 20% at 5 years. There was no evidence of statistical heterogeneity (P = 0.980, I(2 )= 0). AUTHORS' CONCLUSIONS: This analysis shows a significant increase in survival attributable to pre-operative chemotherapy. This is currently the best estimate of the effectiveness of this therapy, but is based on a small number of trials and patients. This analysis was unable to address important questions such as whether particular types of patients may benefit more or less from pre-operative chemotherapy or whether the early stopping of a number of included RCTs impacted on the results. These issues may be addressed by an ongoing individual patient data (IPD) meta-analysis.

Kappa immunoglobulin light chain polymorphisms and survival after allogeneic transplantation for B-cell malignancies: a potential graft-vs-leukaemia target.

In the human leucocyte antigen (HLA)-matched haematopoietic stem cell transplantation (HSCT) setting, minor histocompatibility antigen (mHA) disparities between recipient and donor can lead to graft-vs-host disease (GVHD) or graft rejection. Graft-vs-leukaemia (GVL) effect is a beneficial T-cell-mediated immune response that can also occur following HLA-matched HSCT. mHAs with tissue expression restricted to cells of the haematopoietic system are particularly relevant as immunotherapeutic targets for destroying malignant cells without inducing GVHD. Therefore, it is important to identify further haematopoietic-restricted polymorphic mHAs, which may have the potential to be used clinically for adoptive immunotherapy. Polymorphic mismatching of minor antigens, such as the B-cell-specific protein, the kappa immunoglobulin light chain (kappa) may play a role in the incidence of GVL and therefore the survival of transplant recipients following transplantation for B-cell malignancies. Polymorphisms in the constant region of the immunoglobulin kappa polypeptide chain have been defined involving single amino acid changes at positions 153 and 191. In this study, 51 HLA-matched B-cell malignancy transplant pairs were kappa typed by polymerase chain reaction and restriction enzyme digestion to investigate the association between kappa allotype disparity and outcome after transplantation. Kappa allotype disparity between transplant pairs may be associated with an increased survival compared with pairs not mismatched for kappa, as kappa mismatched recipients had a higher percentage of complete remissions and a decreased level of relapse in comparison with the nonmismatched recipients. HLA peptide prediction software was used to determine which HLA types were the best binders for kappa peptides. It was observed that patients with tissue types predicted to bind the kappa Km(1,2) peptides had better survival outcomes and no relapse compared with those with tissue types not predicted to bind the kappa Km(1,2) peptides. This study may contribute to the assessment of the clinical role of kappa with regard to the outcome of allogeneic transplantation for B-cell malignancies.

CD34+-derived CD11c+ + + BDCA-1+ + CD123+ + DC: expansion of a phenotypically undescribed myeloid DC1 population for use in adoptive immunotherapy.

BACKGROUND: DC are commonly defined as HLA-DR+/Lin- cells that can be CD11c+ + + CD123+/ -, termed DC1/myeloid DC that induce a Th1 response, or CD11c- CD123+ + +, termed DC2/lymphoid DC that induce a Th2 response. However, significant heterogeneity within DC preparations is apparent and supports the existence of several distinct DC subpopulations. This study aimed to expand and characterize CD34+ DC for use in immunotherapy. METHODS: CD34+ cells were seeded at 1 x 10(5)/mL and expanded for 14 days in RPMI + 10% autologous plasma supplemented with GM-CSF, IL-4, Flt-3L and SCF. Maturation was induced with TNF-alpha and PGE2 for 2 days. DC were analyzed morphologically, phenotypically with a panel of MAb to lineage and DC markers, and functionally in MLR, T-cell assays and T-cell cytokine secretion by ELISA. RESULTS: Significant cellular expansion was observed: 60+/-5 x 10(6) DC from 1 x 10(6) CD34+ cells (n=28). Phenotypically DC were characterized as HLA-DR+ +, CD11c+ + +, CD80+ +, CD83+, CD86+ +, CD123+ +, CD15+ +, CD33+ +, BDCA-1+ +, CD4+ and Lin-. DC displayed potent allostimulatory capacity and efficient presentation of KLH and tetanus toxin. DC-primed T cells secreted IFN-gamma (Th1); however, no detectable IL-4 (Th2) was noted. DISCUSSION: We present features of CD34+ DC that have not been previously described. The CD34+ DC generated represent a population of myeloid DC functioning as DC1 but phenotypically expressing markers characteristic of both DC1 and DC2. This novel DC population is capable of inducing naive T-cell responses and can be expanded to clinically useful numbers. CD34+-derived DC represent attractive candidates for use in adoptive T-cell immunotherapy.

Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials.

BACKGROUND: Trials on the effect of systemic chemotherapy on survival and recurrence in adults with high-grade glioma have had inconclusive results. We undertook a systematic review and meta-analysis to assess the effects of such treatment on survival and recurrence. METHODS: We did a systematic review and meta-analysis using updated data on individual patients from all available randomised trials that compared radiotherapy alone with radiotherapy plus chemotherapy. Data for 3004 patients from 12 randomised controlled trials were included (11 published and one unpublished). FINDINGS: Overall, the results showed significant prolongation of survival associated with chemotherapy, with a hazard ratio of 0.85 (95% CI 0.78-0.91, p<0.0001) or a 15% relative decrease in the risk of death. This effect is equivalent to an absolute increase in 1-year survival of 6% (95% CI 3-9) from 40% to 46% and a 2-month increase in median survival time (1-3). There was no evidence that the effect of chemotherapy differed in any group of patients defined by age, sex, histology, performance status, or extent of resection. INTERPRETATION: This small but clear improvement in survival from chemotherapy encourages further study of drug treatment of these tumours.

Preoperative radiotherapy for esophageal carcinoma.

BACKGROUND: The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. OBJECTIVES: This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery and whether or not any pre-defined patient subgroups benefit more or less from preoperative radiotherapy SEARCH STRATEGY: Medline and CancerLit searches were supplemented by information from trial registers and by hand searching relevant meeting proceedings and by discussion with relevant trialists, organisations and industry. The search strategy was run again in Medline, Embase and the Cochrane Library on 2nd May 2000, one year after original publication. No new trials were found. SELECTION CRITERIA: Trials were eligible for inclusion in this meta-analysis provided they randomized patients with potentially resectable carcinoma of the esophagus (of any histological type) to receive radiotherapy or no radiotherapy prior to surgery. Trials must have used a randomization method which precluded prior knowledge of treatment assignment and completed accrual by December 1993, to ensure sufficient follow-up by the time of the first analysis (September 1995). DATA COLLECTION AND ANALYSIS: A quantitative meta-analysis using updated data from individual patients from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. This approach was used to assess whether preoperative radiotherapy improves overall survival and whether it is differentially effective in patients defined by age, sex and tumour location. MAIN RESULTS: With a median follow-up of 9 years, in a group patients with mostly squamous carcinomas, the hazard ratio (HR) of 0.89 (95% CI 0.78-1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p=0.062). No clear differences in the size of the effect by sex, age or tumor location were apparent. REVIEWER'S CONCLUSIONS: Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients (90% power, 5% significance level) would be needed to reliably detect such an improvement (from 15 to 20%).

Is there bias in the publication of individual patient data meta-analyses?

OBJECTIVE: There is increasing empirical evidence for the existence of bias in the publication of primary clinical research, with statistically significant results being published more readily, more quickly, and in higher impact journals. Meta-analysis of individual patient data (IPD) may represent a gold standard of "secondary" clinical research, giving the best possible summary of current evidence for a particular question, but publication of these may also be subject to bias. This study aimed to explore which factors might be associated with publication of IPD meta-analyses and to identify potential sources of bias. METHODS: For all known IPD meta-analysis projects in cancer, the responsible investigator was surveyed by means of a questionnaire to determine descriptive characteristics of the meta-analysis, the nature of the results, and details of the publication history. RESULTS: There is no good evidence that overall publication status of meta-analyses in cancer is dependent on the statistical or clinical significance of the results. However, those meta-analyses with nonsignificant results did seem to take longer to publish and were published in lower impact journals compared with those with more striking results. CONCLUSIONS: Based on the current data, there seems to be no strong association between the results of IPD meta-analyses in cancer and publication.

Preoperative radiotherapy for esophageal carcinoma. Oeosphageal Cancer Collaborative Group.

BACKGROUND: The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. OBJECTIVES: This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery and whether or not any pre-defined patient subgroups benefit more or less from preoperative radiotherapy SEARCH STRATEGY: Medline and CancerLit searches were supplemented by information from trial registers and by hand searching relevant meeting proceedings and by discussion with relevant trialists, organisations and industry. SELECTION CRITERIA: Trials were eligible for inclusion in this meta-analysis provided they randomized patients with potentially resectable carcinoma of the esophagus (of any histological type) to receive radiotherapy or no radiotherapy prior to surgery. Trials must have used a randomization method which precluded prior knowledge of treatment assignment and completed accrual by December 1993, to ensure sufficient follow-up by the time of the first analysis (September 1995). DATA COLLECTION AND ANALYSIS: A quantitative meta-analysis using updated data from individual patients from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. This approach was used to assess whether preoperative radiotherapy improves overall survival and whether it is differentially effective in patients defined by age, sex and tumour location. MAIN RESULTS: With a median follow-up of 9 years, in a group patients with mostly squamous carcinomas, the hazard ratio (HR) of 0.89 (95% CI 0.78-1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p=0.062). No clear differences in the size of the effect by sex, age or tumor location were apparent. REVIEWER'S CONCLUSIONS: Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients (90% power, 5% significance level) would be needed to reliably detect such an improvement (from 15 to 20%).

Autologous stem cell transplantation for malignancy: a systematic review of the literature.

A systematic review of the literature was undertaken to assess what published evidence is currently available to support the increasing use of autologous stem cell transplantation (ASCT), and to evaluate the published data with regard to the comparative cost of high-dose and conventional therapy. The review aimed to identify all published, randomized controlled trials (RCTs) comparing high-dose therapy (HDT) with ASCT versus conventional chemotherapy (CC) in acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, and breast, lung, testicular and ovarian cancer. The review also aimed to identify all studies that had compared the cost of the two treatment strategies. Reports were identified by systematic searches of Cancerlit, Embase and Medline, and handsearching of several conference proceedings. Where possible, pooled odds ratios (ORs) were calculated according to the fixed-effect model. A total of 18 randomized trials were identified in acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, and breast, lung and testicular cancer. Trials were generally small and no disease site had sufficient information to determine reliably whether high-dose therapy with autologous transplant is more effective than CC. Five studies were identified that compared the cost of the two treatments. These found the cost of HDT to be between one and four times higher than that of CC. Further randomized trials are required. Where appropriate, these should include economic assessment and assessments of long-term toxicity.

Evaluation and management of the "red face". Interview by K. Watsky and M. Rothe.

Patients presenting with a "red face" challenge clinicians to consider a broad differential diagnosis that includes contact dermatitis. The diagnosis may be obscured or complicated by underlying actinic damage or rosacea. Unraveling this Gordian knot to arrive at a precise and accurate diagnosis takes patience and practice. The collective experience of our invited group of expert clinicians sheds light on this process.

Can the published data tell us about the effectiveness of neoadjuvant chemotherapy for locally advanced cancer of the uterine cervix?

The effect of neoadjuvant chemotherapy on survival of patients with locally advanced cervical cancer was investigated by conducting a systematic review and meta-analysis of the published data. Of the 21 randomised trials that we identified, only 15 were published. Furthermore, 2-year survival data could be extracted from only seven trial reports and 3-year survival from only nine trial reports. Meta-analyses of the published data at 2 and 3 years are neither clearly in favour of neoadjuvant chemotherapy nor control (2 years: odds ratio (OR) = 1.09, 95% confidence interval (CI) = 0.83-1.45, P = 0.37; 3 years: OR = 0.96, 95% confidence interval (CI) = 0.73-1.25, P = 0.45). Being restricted to only some of the data from a relatively small fraction of the randomised trials, these analyses potentially suffer from a number of biases and are therefore inconclusive. The only reliable way to judge the value of neoadjuvant chemotherapy in this disease is to perform a meta-analysis of centrally collected, updated, individual data on all patients from all known randomised trials. Such an analysis is currently being carried out by an international collaborative group.

Species-specific distribution of alpha-galactosyl epitopes on the gastric H/K ATPase beta-subunit: relevance to the binding of human anti-parietal cell autoantibodies.

The gastric H/K ATPase beta-subunit, an abundant glycoprotein of the secretory membranes of gastric parietal cells, is the major autoantigen recognized by human parietal cell autoantibodies in gastric autoimmunity. Our previous studies demonstrated that the human autoantibodies recognize the H/K ATPase beta-subunit from a number of species and that glycosylation of the beta-subunit with complex N-glycans is required for autoantibody binding. The N-glycans of the beta-subunit contain polylactosamine chains. The lactosamine chains of the rabbit beta-subunit are terminated with alpha-linked galactosyl residues (alpha-galactosyl epitope) (Tyagarajan et al., Biochemistry, 1996, 35, 3238-3246). Here we have investigated the expression of alpha-galactosyl epitopes on the H/K ATPase beta-subunit from a number of species. Using the alpha-galactosyl binding lectin, BS1-IB4, and naturally occurring anti-alpha-galactosyl antibodies, we have demonstrated that the rat H/K ATPase beta-subunit also contains terminal alpha-galactosyl residues, but not the beta-subunit from pig, dog, and mouse, indicating species-specific differences in the terminal saccharide sequences of the beta-subunit. We also investigated the potential contribution of the alpha-galactosyl epitopes to the binding by human sera. The reactivity of human pernicious anemia serum with gastric parietal cells could not be inhibited with saccharide inhibitors and, in addition, no binding was observed with normal human sera. We conclude that the H/K ATPase beta-subunit oligosaccharides from rabbit and rat are terminated with alpha-galactosyl epitopes, and although the presence of this epitope does not contribute to binding by human parietal cell autoantibodies at the concentrations routinely used, it is recommended that neither rat or rabbit stomachs be used for screening human sera.

Preoperative radiotherapy in esophageal carcinoma: a meta-analysis using individual patient data (Oesophageal Cancer Collaborative Group).

PURPOSE: The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery. METHODS AND MATERIALS: This quantitative meta-analysis included updated individual patient data from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. RESULTS: With a median follow-up of 9 years, the hazard ratio (HR) of 0.89 (95% CI 0.78-1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p = 0.062). No clear differences in the size of the effect by sex, age, or tumor location were apparent. CONCLUSION: Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients would be needed to reliably detect such an improvement (15-->20%).

Meta-analyses using individual patient data.

Systematic reviews of randomized controlled trials often provide the most reliable information on which to base treatment policy. However, to be reliable, such reviews need to contain a high proportion of all the relevant randomized evidence. This relates both to the need to find all trials and the need to analyse data on all participants. One way to achieve this is through a collaboration in which those responsible for the trials supply data on each randomized patient for an individual patient data meta-analysis. However, such projects require more time and resources than more conventional reviews and are still rare. This paper illustrates how they can help to achieve the aim of using complete data in a systematic review.

Comparison of in vivo and in vitro measures of beryllium sensitization.

Chronic beryllium disease (CBD) diagnosis hinges on demonstrating a cell-mediated immune response to beryllium salts in vitro with the beryllium lymphocyte proliferation test (BeLPT). The BeLPT has found widespread application in screening for CBD and beryllium sensitization in populations of exposed workers. We hypothesized that the in vivo beryllium salt patch test may be of value as an adjunct to the BeLPT, rectifying false negative or ambiguous blood test results. We studied subjects with CBD (n = 11), beryllium sensitization without disease (n = 3), and control subjects with dermatitis (n = 20). Evaluation included completion of a demographic questionnaire, blood BeLPT (if CBD or beryllium-sensitized), and beryllium patch testing with 0.1% and 1% beryllium sulfate (BeSO4) in petrolatum and in aqueous vehicles. Biopsies were performed at abnormal patch test sites in five subjects. The 1% aqueous BeSO4 proved superior either to 1% petrolatum or 0.1% solutions, producing positive reactions in all CBD and beryllium-sensitized subjects. We observed no long-term adverse reactions. Biopsies demonstrated spongiotic changes early, followed by noncaseating granulomas within 18 days. We conclude that the beryllium patch test can be used safely to clarify the sensitization state and diagnosis of CBD.

Thirty years of Medical Research Council randomized trials in solid tumours.

This paper reviews the survival outcome from the randomized Phase III trials in solid tumours published on behalf of, or in collaboration with, the Cancer Therapy Committee (CTC) of the British Medical Research Council over a 30-year period to 31 December 1995. We review briefly the innovations in statistical methodology that have occurred over the period. We also note the ways in which standards of reporting the trials have improved, with more recent publications including, for example, estimates of the size of effect and confidence intervals. In all, 32 trials, involving over 5000 deaths in more than 8000 patients, have been published. Tumour types have included bladder, bone, brain, cervix, colon and rectum, head and neck, kidney, lung, ovary, prostate and skin. This paper presents a bibliography of these trials and gives details of the treatment comparisons made, the numbers of patients randomized and included in the analysis for each treatment arm, the observed numbers of deaths, and an estimate of the hazard ratio with associated 95% confidence intervals. The bibliography also indicates the main endpoint of each trial, whether recurrence-free survival or survival, and whether the trial was aimed at finding a difference or showing equivalence. The MRC trials have made an impact on both clinical practice and research activities. For example, the lung cancer programme has helped to establish the role of chemotherapy in small cell lung cancer and has developed better palliative treatment for non-small cell lung cancer. Trials of the radiosensitizer misonidazole have demonstrated that it has no role in the treatment of a number of cancers, trials of hyperbaric oxygen have defined the biological activity of this approach, and the appropriate dose of radiotherapy in patients with brain tumours has been found. The individual trials recruited between 44 and 824 patients (median 213). A better measure of the information in a trial is the number of deaths reported, which varied from 28 to 661 (median 145). A large proportion of the comparisons (8/29 or 28%) anticipating a survival difference, demonstrated such a difference at the 5% level of significance. Despite this, it is concluded that some of the trials should have been larger. In such cases, hindsight suggests either that an overoptimistic view of the anticipated survival benefit was taken at the design stage, or, for equivalence trials, the planned confidence interval was too wide for definitive statements to be made. As a consequence, the current CTC profolio of ongoing randomized trials open to patient accrual at 1 January 1996 have a projected median size of 600 and range from 120 to 2000 patients.