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PubMed2005

Oximes for acute organophosphate pesticide poisoning.

BACKGROUND: Acute organophosphorus pesticide poisoning causes tens of thousands of deaths each year across the developing world. Standard treatment involves administration of intravenous atropine and oxime to counter acetylcholinesterase inhibition at the synapse. The usefulness of oximes, such as pralidoxime and obidoxime, has been challenged over the past 20 years by physicians in many parts of the world, who have failed to see benefit in their clinical practice. OBJECTIVES: To find the clinical trial evidence for oximes producing clinical benefit in acute organophosphorus pesticide-poisoned patients. SEARCH STRATEGY: We carried out a systematic search to find randomised clinical trials (RCTs) of oximes in acute organophosphorus pesticide poisoning, using MEDLINE, EMBASE and Cochrane databases. All articles with the text words 'organophosphate' or 'oxime' together with 'poisoning' or 'overdose' were examined. (Search last updated November 2003.) SELECTION CRITERIA: Articles that could possibly be randomised clinical trials were retrieved to determine if this was the case. DATA COLLECTION AND ANALYSIS: The published methodology of the possible RCTs located is not clear. One was found in abstract form only and two other published trials also had many gaps in the published methodology. We have attempted to contact the principal authors of all three trials but have been unable to obtain further information. MAIN RESULTS: Two RCTs have been published, involving 182 patients treated with pralidoxime. These trials did not find benefit. However, the studies did not take into account a number of issues important for outcome and the methodology is unclear. Therefore, a generalised statement on effectiveness cannot be supported by the published results. In particular, characteristics at baseline were not evenly balanced, the dose of oxime was much lower than recommended in guidelines, there were substantial delays to treatment, and the type of organophosphate was not taken into account. The abstract of the third trial, a small possible RCT, is uninterpretable without further data. AUTHORS' CONCLUSIONS: Current evidence is insufficient to indicate whether oximes are harmful or beneficial in the management of acute organophosphorus pesticide poisoning. A much larger RCT is required to compare the World Health Organization recommended pralidoxime regimen (>30 mg/kg bolus followed by >8 mg/kg/hr infusion) with placebo. There are many theoretical and practical reasons why oximes may not be useful to patients with overwhelming self-poisoning. Such a study will need to be designed with pre-defined sub-group analysis to allow identification of patient sub-groups that may benefit from oximes.

Antidotes↗

PubMed2006

Influenza vaccination for healthcare workers who work with the elderly.

BACKGROUND: Healthcare workers (HCW) (nurses, doctors, other health professionals, cleaners and porters), have substantial rates of clinical and sub-clinical influenza during influenza seasons and may transmit influenza to those in their care, especially the vulnerable elderly. OBJECTIVES: To identify and summarise comparative studies assessing the effects of vaccinating healthcare workers (HCW) on the incidence of influenza, influenza-like-illness (ILI) and its complications on elderly residents in long-term facilities. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Database of Systematic Reviews and the NHS Database of Abstracts of Reviews of Effectiveness (DARE) (The Cochrane Library Issue 1, 2006); MEDLINE (January 1966 to Week 1, February 2006); EMBASE (1974 to March 2006); Biological Abstracts (1969 to December 2004); and Science Citation Index-Expanded (1974 to March 2006). SELECTION CRITERIA: Comparative randomised and non-randomised studies reporting the effects of influenza vaccines on the incidence of viral infections in institutions for the elderly of any type, in any schedule of vaccination given to HCW caring for elderly residents of long-term facilities aged 60 years or older. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the methodological quality using criteria from the Cochrane Reviewers' Handbook and the Newcastle-Ottawa scale (for non-randomised studies). MAIN RESULTS: We included two cluster randomised controlled trials (C-RCT) and one cohort study. Staff vaccination appears to have significant effect against ILI (absolute vaccine efficacy (VE) 86%, 95% confidence interval (CI) 40% to 97%) only when patients are vaccinated too; if patients are not vaccinated, staff immunisation shows no effect (based on one C-RCT). Based on a small number of observations from two C-RCTs, the vaccines have no efficacy against influenza (odds ratio (OR) 0.86, 95% CI 0.44 to 1.68) or lower respiratory tract infections (OR 0.70, 95% CI 0.41 to 1.20) but were effective against deaths from pneumonia (VE 39%, 95% CI 2% to 62%) and deaths from all causes (VE 40%, 95% CI 27% to 50%). All findings must be interpreted with caution given the presence of selection bias. AUTHORS' CONCLUSIONS: We concluded that there is no credible evidence that vaccination of healthy people under the age of 60, who are HCWs caring for the elderly, affects influenza complications in those cared for. However, as vaccinating the elderly in institutions reduces the complications of influenza and vaccinating healthy persons under 60 reduces cases of influenza, those with the responsibility of caring for the elderly in institutions may want to increase vaccine coverage and assess its effects in well-designed studies.

Adult↗

PubMed2005

Risperidone versus olanzapine for schizophrenia.

BACKGROUND: Antipsychotic medication is a mainstay of treatment for schizophrenia and risperidone and olanzapine are the most popular treatment choice of the new generation drugs. OBJECTIVES: To determine the clinical effects, safety and cost effectiveness of risperidone compared with olanzapine for treating schizophrenia. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (June 2004) which is based on regular searches of, amongst others, BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO. References of all identified studies were inspected for further trials. We also contacted relevant pharmaceutical companies for additional information. SELECTION CRITERIA: We included all clinical randomised trials comparing risperidone with olanzapine 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/harm (NNT/H) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD). MAIN RESULTS: We found no difference for the outcome of unchanged or worse in the short term (n=548, 2 RCTs, RR 1.00 CI 0.88 to 1.15). One study, sponsored by the manufactures of olanzapine, favoured this drug for the outcome of relapse/rehospitalisation by 12 months (n=279, RR 2.16 CI 1.31 to 3.54, NNT 7 CI 4 to 25). Most mental state data showed the two drugs to as effective as each other (n=552, 2 RCTs, RR 'no <20% decrease PANSS by eight weeks' 1.01 CI 0.87 to 1.16). At least two thirds of people given risperidone or olanzapine experienced an adverse event (n=300, 2 RCTs, RR 1.16 CI 0.70 to 1.94). About 20% had anticholinergic symptoms (n=719, 3 RCTs, RR 1.12 CI 0.77 to 1.63) and 20% of both groups experienced insomnia (n=594, 3 RCTs, RR 1.33 CI 0.95 to 1.85) and approximately 33% sleepiness (n=719, 4 RCTs, 0.99 CI 0.79 to 1.23). One third of people given either drug experienced some extrapyramidal symptoms (n=893, 3 RCTs, RR 1.18 CI 0.75 to 1.88) but 25% of people using risperidone require medication to alleviate extrapyramidal adverse effects (n=419, 2 RCTs, RR 1.76 CI 1.25 to 2.48, NNH 8 CI 4 to 25). People allocated to risperidone were less likely to gain weight compared with those given olanzapine and the weight gain resulting from olanzapine can be considerable and of rapid onset (n=377, 1 RCT, RR gain more than 7% of their baseline weight 0.40 CI 0.23 to 0.70, NNT 8 CI 6 to 17). Risperidone may cause more sexual dysfunction than olanzapine (n=370, 2 RCTs, RR abnormal ejaculation 4.36 CI 1.38 to 13.76, NNH 20 CI 6 to 176; n=31, 1 RCT, RR impotence 2.43 CI 0.24 to 24.07). Within trials both drugs are associated with equal attrition (n=1217, 7 RCTs, RR leaving the study early 1.17 CI 0.92 to 1.49). AUTHORS' CONCLUSIONS: Data regarding quality of life and economic outcomes are difficult to interpret, and for both these highly marketed new drugs we know very little from evaluative studies regarding service outcomes, general functioning and behaviour, engagement with services and treatment satisfaction. There is little to differentiate between risperidone and olanzapine except on the issue of adverse effects and both these drugs have unpleasant adverse effects. Risperidone is particularly associated with movement disorders and sexual dysfunction. Olanzapine can cause considerable rapid weight gain.This review highlights the need for large, independent, well designed, conducted and reported pragmatic randomised studies.

Antipsychotic Agents↗

PubMed2006

Structured treatment interruptions (STI) in chronic unsuppressed HIV infection in adults.

BACKGROUND: Structured treatment interruptions (STI) of antiretroviral therapy (ART) have been investigated as part of novel treatment strategies, with different aims and objectives depending on the populations involved. These populations include: 1) patients who initiate ART during acute HIV infection; 2) patients with chronic HIV infection, on ART, with successfully suppressed viremia; and 3) patients with chronic HIV infection and treatment failure, with persistent viremia due to multi-drug resistant HIV (Hirschel 2001; Deeks 2002; Miller 2003). In an earlier Cochrane review (Pai 2005), we had summarized the evidence about the effects of STI in chronic suppressed HIV infection. In this review, we summarize the evidence on STI in patients with chronic unsuppressed HIV infection due to drug-resistant HIV. Unsuppressed HIV infection describes those patients who cannot suppress viremia, due to the presence of multi-drug-resistant virus. It is also referred to as treatment failure. Drug resistance is identified by the presence of resistant mutations at baseline.STI as a treatment strategy in HIV-infected patients with chronic unsuppressed viremia involves interrupting ART in controlled clinical settings, for a pre-specified duration of time. These interruptions have various aims, including the following: 1) to allow wild virus to re-emerge and replace the resistant mutant virus, with the hope of improving the efficacy of a subsequent ART regimen; 2) to halt development of drug resistance and to preserve subsequent treatment options; 3) to alleviate treatment fatigue and reduce drug-related adverse effects; and 4) to improve quality of life (Miller 2003; Montaner 2001; Vella 2000;). OBJECTIVES: The objective of our systematic review was to synthesize the evidence on the effect of structured treatment interruptions in adult patients with chronic unsuppressed HIV infection. SEARCH STRATEGY: We included all available intervention studies (randomized controlled trials and non-randomized trials) conducted in HIV-infected patients worldwide. We searched nine databases, covering the period from January 1996 to February 2006. We also scanned bibliographies of relevant studies and contacted experts in the field to identify unpublished research, abstracts and ongoing trials. In the first screen, a total of 3186 potentially eligible citations from nine databases and sources were identified, of which 2047 duplicate citations were excluded. The remaining 1139 citations were examined in detail, and we further excluded 951 citations that were modeling studies, animal studies, case reports, and opinion pieces. As shown in Figure 01, 188 citations were identified in the second screen as relevant for full-text screening. Of these, 60 basic science studies, editorials and abstracts were excluded and 128 full-text articles were retrieved. In the third screen, all full-text articles were examined for eligibility in our review. These were subclassified into three categories: 1) chronic suppressed HIV infection; 2) chronic unsuppressed HIV infection; and 3) acute HIV infection. Studies were further excluded if their abstracts did not contain enough information for inclusion in our reviews. A total of 62 studies were finally classified into chronic suppressed, acute, and chronic unsuppressed categories. Of these, 17 trials met the eligibility criteria for this review. SELECTION CRITERIA: Inclusion criteriaAll available randomized or non-randomized controlled trials investigating planned treatment interruptions among patients with chronic unsuppressed HIV infection. Early pilot non-randomized prospective studies on treatment interruptions of fixed and variable durations were also included. Relevant abstracts on randomized controlled trials were also included if they contained sufficient information. Exclusion criteriaEditorials, reviews, modeling studies, and basic science studies were excluded. Studies on STI among patients with chronic suppressed HIV infection were summarized in a separate review. Studies on STI in primary HIV infection were beyond the scope of this review. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data, evaluated study eligibility and quality. Disagreements were resolved in consultation with a third reviewer.A total of seventeen studies on STI were included in our review. However, due to significant heterogeneity across studies (i.e. in study design, populations, baseline characteristics, and reported outcomes; and in reporting of measures of effect, hazard ratios, and risk ratios), we considered it inappropriate to perform a meta-analysis. MAIN RESULTS: In early pilot non-randomized trials, a pattern was evident across studies. During treatment interruption, a decline in CD4 cell counts, increase in viral load, and a shift in the level of genotypic drug resistance towards more of a wild-type HIV virus was reported. This suggests that STI may be used to increase drug susceptibility to an optimized salvage regimen upon treatment re-initiation. These studies generated useful data and hypotheses that were later tested in randomized controlled trials. Randomized controlled trials rated high on quality. Of the eight randomized controlled trials reviewed, seven had been completed while one was ongoing and remains blinded. Of the seven completed randomized controlled trials, six have reported consistent virologic and immunologic patterns, and found no significant benefit in virologic response to subsequent ART in the STI arm, compared to the control arm. In addition, the largest completed randomized trial reported greater numbers of clinical disease progression events and evidence of prolonged negative impact on CD4 cell counts in the STI arm (Beatty 2005; Benson 2004; Deeks 2001; Lawrence 2003; Walmsley 2005; Ruiz 2003). The single RCT with divergent findings from the others (GigHAART), reporting a significant virologic and immunologic benefit due to STI, was different in prescribing a shorter STI duration and a salvage ART regimen of 8-9 drugs. There were also differences in the patient population characteristics with this study, targeting those with very advanced HIV disease (Katlama 2004). Although we await the unblinded results of the eighth RCT (OPTIMA), the evidence so far does not support STI in the setting of chronic unsuppressed HIV infection with antiretroviral treatment failure (Brown 2004; Holodniy 2004; Kyriakides 2002; Singer 2006). AUTHORS' CONCLUSIONS: The current available evidence primarily supports a lack of benefit of STI before switching therapy in patients with unsuppressed HIV viremia despite ART. There is evidence of harm in attempting STI in patients with relatively advanced HIV disease, due to the associated CD4 cell decline and the increased risk of clinical disease progression. At this time, there is no evidence to recommend the use of STI in this clinical category of patients with treatment failure.

Adult↗

PubMed1996

The efficacy of dexamethasone iontophoresis for the treatment of rheumatoid arthritic knees: a pilot study.

OBJECTIVE: To examine the efficacy of dexamethasone sodium phosphate (DEX) iontophoresis for the treatment of rheumatoid arthritis (RA) of the knee, and to obtain statistical information for a future randomized controlled trial (RCT). METHODS: Ten subjects with RA, ranging in age from 34-75, were randomly assigned to either the experimental or placebo group. Iontophoresis treatments were given to both groups on days 1, 3, and 5. Five subjects in the experimental group received a mixture of 1 ml of DEX (4 mg/ml) and 1 ml of injectable sterile water; those in the placebo group received 2 ml of saline solution. Pain on movement, at rest, and on pressure, active joint count, and active range of motion, were evaluated on days 1, 5, and 20. The patient's global assessment of treatment efficacy was also assessed on days 5 and 20. Mann-Whitney U tests and Friedman two-way analyses of variance were performed for statistical analyses. RESULTS: Pain at rest was found to be statistically different between the two groups (P = 0.0317). Statistical significance was also found over time for pain on movement within the experimental group (P = 0.0224). CONCLUSION: The results suggest that DEX iontophoresis is more effective than placebo in relieving pain at rest and on movement in the RA knee. Based on the study data, a total of 40 subjects will be required for an RCT of a similar nature.

Activities of Daily Living↗

PubMed1999

Sonography and magnetic resonance imaging equivalent for the assessment of full-thickness rotator cuff tears.

OBJECTIVE: To investigate the diagnostic value of sonography (SG) and magnetic resonance imaging (MRI) in the assessment of full-thickness rotator cuff tears (RCTs). METHODS: Twenty-one consecutive, otherwise healthy patients with noninflammatory unilateral chronic (>3 months) shoulder complaints due to a possible full-thickness RCT were studied (9 women and 12 men, mean +/- SD age 56 +/- 12). According to standardized procedures, SG was performed by both a radiologist and a rheumatologist, and MRI was evaluated by 2 radiologists. All assessors were blinded to the patient's diagnosis. Within 3 weeks after SG and MRI, arthroscopy was performed. SG, MRI, and arthroscopy results were scored as negative or positive for the presence of a full-thickness RCT. The result of surgical inspection was used as the "gold standard." RESULTS: For full-thickness RCTs, the sensitivity was 0.81 for SG and 0.81 for MRI. The specificity was 0.94 for SG and 0.88 for MRI. The positive predictive value was 0.96 for SG and 0.91 for MRI. The negative predictive value was 0.77 for SG and 0.74 for MRI. Accuracy was 0.86 for SG and 0.83 for MRI. CONCLUSION: Full-thickness RCTs can be identified accurately by both SG and MRI. Because of its low cost and because it can be performed in the rheumatology unit, SG seems to be a promising diagnostic tool for use by the rheumatologist.

Adult↗

PubMed2006

Risk evaluation of carriers with chromosome reciprocal translocation t(7;13)(q34;q13) and concomitant meiotic segregation analyzed by FISH on ejaculated spermatozoa.

We performed the segregation analysis of a relatively large pedigree of t(7;13)(q34;q13) carriers together with the sperm karyotype analysis of the one carrier using a tri-color fluorescence in situ hybridization (FISH) method. The risk assessments for unfavorable pregnancy outcomes in a series of 36 pregnancies in eight reciprocal chromosome translocation (RCT) couples of carriers were estimated directly from a pedigree after ascertainment correction. The individual probability rate for unbalanced child was predicted according to Stengel-Rutkowski and co-workers. The unbalanced karyotypes in the form of monosomy 7q34-->qter and trisomy 13q13-->qter were detected among stillborn/early death newborns with holoprosencephaly (HPE), cyclopia and other malformations. Based on clinical description of unkaryotyped stillbirth progeny, it can be assumed that the phenotype distinctions were connected with the unbalanced karyotype from 2:2 segregation (monosomy 7q with trisomy 13q) and 3:1 segregation as interchange trisomy 13 (Patau syndrome). Probability rates for miscarriages, stillbirth/early death were 12.9 +/- 6% (4/31) and 29 +/- 8.2% (9/31), respectively. The results of the meiotic segregation pattern indicated the rate of unbalanced spermatozoa for about 60%, with the unusual high rate (29.4%) of 3:1 segregant (i.e., 13.4% of the tertiary segregation and 16% of the interchange segregation). Adjacent-1 segregation followed with 23.5% and adjacent-2 followed with 7.2% of analyzed spermatozoa. The high rate of unbalanced gametes in comparison to the number of stillborn/early death and miscarriages detected in pedigree suggests a strong selection against unbalanced chromosomal constitutions during fetal development. It corresponds to a very small probability rate (about 0.3%) of viable unbalanced progeny from 3:1 meiotic segregation predicted for maternal carriers. This knowledge can be used in genetic counseling of families with similar RCT ascertained in a different way.

Abortion, Spontaneous↗

PubMed1985

A score system for evaluating random control clinical trials of prophylaxis of abdominal surgical wound infection.

We devised 33 rules for the evaluation of random control trials (RCT) and used them to assess 56 RCTs listed in Index Medicus during 1980-82 on antibiotic prophylaxis of surgical wound infection. We asked 15 questions about design and conduct, 10 about analysis and 8 about presentation. Out of a maximum score of 100 only 16 papers scored over 70, the highest being 89 and the lowest 34. Defects in presentation were not common, and 17 papers scored over 90 per cent. Defects in analysis included the incorrect use of statistical tests and ignoring the Type II error in 'negative' trials; only 13 papers scored over 70 per cent. Defects in design and conduct included transgressions of ethical principles, inappropriate regimens, ill-defined end points and biased randomization or assessment; only 20 papers scored over 70 per cent. We conclude that there is room for improvement in the performance of RCT and that the application of the 33 rules would be helpful not only to researchers but also to editors and referees of scientific journals, and to their readers.

Abdomen↗

PubMed2002

Quantitative morphology of full thickness rotator cuff tears.

The occurrence of full thickness rotator cuff tears (RCTs) at time of death, the size and distribution of those tears among the tendons of the rotator cuff, and the anterior to posterior and medial to lateral dimensions of the RCTs were determined. A subset of 57 shoulders from a group of 414 were found to have full thickness rotator cuff tears. The three-dimensional coordinates of specific bony landmarks and points defining the circumference of the RCT were digitized using a Flock of Birds DC electromagnetic tracking device. Bony landmarks were used to determine the separation between adjacent tendons of the rotator cuff. Points describing the circumference of the RCT were used to calculate the area of the tear. The majority of tears occurred in the supraspinatus tendon alone (25), or in both the supraspinatus and infraspinatus tendons (22). The areas of the RCTs ranged from 0.07 cm(2) to 19.17 cm(2) with an average of 4.43 cm(2). The mean anterior to posterior length was 1.95 cm. The mean medial to lateral length was 1.98 cm.

Aged↗

PubMed2002

Randomized controlled trials of continuing medical education: what makes them most effective?

INTRODUCTION: It is essential that professional standards of excellence are demonstrated in the continuing medical education (CME) curriculum and research. METHODS: This review examines 20 randomized controlled trial (RCT) studies in CME and their effect on physician performance and/or patient health care outcomes. A systematic evaluation of the 20 RCT articles was performed. The investigators of the trials were interviewed using a standardized interview schedule. Citations from science and social science publications were compiled to obtain an unobtrusive measure of the influence of the trials. RESULTS: Investigators were most often motivated to build on earlier research of others, their own earlier research, or a combination of others' earlier research and their own. The most effective educational strategies used multiple interventions, two-way communications, printed and graphic materials in person, and locally respected health personnel as educators. Statistically significant findings more often related to physician performance than to patient health care outcomes. The most effective studies were the ones in which the educational methods were cost effective, findings could be generalized to other physician groups, the studies were implemented elsewhere in multisite health care and health-related programs and had the most citations. Investigators interviewed about their RCTs provided advice for future directions of CME curriculum development and research. DISCUSSION: CME program directors should determine what physicians need to learn, should reach out to nonparticipating physicians, and should focus on relevant problem areas. These problem areas should be ones in which it is possible to make changes, particularly in patient health care outcomes.

Curriculum↗

PubMed2004

Conservative treatment of invasive bladder carcinoma by transurethral resection, protracted intravenous infusion chemotherapy, and hyperfractionated radiotherapy: long term results.

BACKGROUND: Organ preservation has been investigated in patients with muscle-invasive bladder carcinoma over the past decades as an alternative to radical cystectomy. The majority of studies reported that trimodal schedules, including transurethral resection of bladder tumor (TURB), radiotherapy (RT), and chemotherapy, are a feasible and safe organ-sparing approach without deferring the survival probability. However, to the authors' knowledge the best combination of RT and chemotherapy has yet to be well defined. The current study evaluated the long-term results of a schedule of concurrent cisplatin and 5-fluorouracil (5-FU) administered as protracted intravenous infusions (PVI) during hyperfractionated radiotherapy (HFRT) with organ-sparing intent in patients with infiltrating transitional cell carcinoma of the bladder (TCCB). METHODS: Seventy-seven patients with a classification of T2-T4aN0M0 TCCB were enrolled in the current study. After a complete TURB and bladder mapping, 42 of 77 patients underwent 2 cycles of induction chemotherapy. All 77 patients underwent HFRT and a schedule of cisplatin (4-6 mg/m(2) per day) and 5-FU (180-220 mg/m(2) per day) as concomitant PVI (radiochemotherapy [RCT]). Six to 8 weeks after RCT, patient response was evaluated by computed tomography scan, urine cytology, and TURB. Patients who achieved a complete response (CR) were followed at regular intervals. For patients with residual or recurrent invasive tumor, salvage cystectomy was recommended. RESULTS: Seventy-two patients were evaluable for response: 65 achieved a CR (90.3%) and 7 (9.7%) achieved a partial response. No significant difference was observed for the different prognostic factors with the exception of stage of disease (T2 [95.7%] vs. T3-T4a [80.0%]; P = 0.04). The observed toxicity, mainly hematologic, was higher among the patients who received induction chemotherapy compared with the patients who did not receive induction chemotherapy, even though the difference was not statistically significant. After a median follow-up of 82.2 months (range, 30-138 months), 44 of 65 (57.1%) patients who achieved a CR were alive. Of these 44 patients, 33 had tumor-free bladders. The 5-year overall, bladder-intact, tumor-specific, disease-free, and cystectomy-free survival rates for all 77 patients were 58.5%, 46.6%, 75.0%, 53.5%, and 76.1%, respectively. No associations were observed in overall and tumor-specific survival with different prognostic factors. CONCLUSIONS: Combined treatment appeared to provide high response rates and can be offered as an alternative option to radical cystectomy in selected patients who refuse or are unsuitable for surgery.

Adult↗

PubMed2003

An exploratory instrumental variable analysis of the outcomes of localized breast cancer treatments in a medicare population.

This study is motivated by the potential problem of using observational data to draw inferences about treatment outcomes when experimental data are not available. We compare two statistical approaches, ordinary least-squares (OLS) and instrumental variables (IV) regression analysis, to estimate the outcomes (three-year post-treatment survival) of three treatments for early stage breast cancer in elderly women: mastectomy (MST), breast conserving surgery with radiation therapy (BCSRT), and breast conserving surgery only (BCSO). The primary data source was Medicare claims for a national random sample of 2907 women (age 67 or older) with localized breast cancer who were treated between 1992 and 1994. Contrary to randomized clinical trial (RCT) results, analysis with the observational data found highly significant differences in survival among the three treatment alternatives: 79.2% survival for BCSO, 85.3% for MST, and 93.0% for BCSRT. Using OLS to control for the effects of observable characteristics narrowed the estimated survival rate differences, which remained statistically significant. In contrast, the IV analysis estimated survival rate differences that were not significantly different from 0. However, the IV-point estimates of the treatment effects were quantitatively larger than the OLS estimates, unstable, and not significantly different from the OLS results. In addition, both sets of estimates were in the same quantitative range as the RCT results.We conclude that unadjusted observational data on health outcomes of alternative treatments for localized breast cancer should not be used for cost-effectiveness studies. Our comparisons suggest that whether one places greater confidence in the OLS or the IV results depends on at least three factors: (1) the extent of observable health information that can be used as controls in OLS estimation, (2) the outcomes of statistical tests of the validity of the instrumental variable method, and (3) the similarity of the OLS and IV estimates. In this particular analysis, the OLS estimates appear to be preferable because of the instability of the IV estimates.

Aged↗

PubMed2004

The changing face of HIV-associated lymphoma: what can we learn about optimal therapy inl the post highly active antiretroviral therapy era?

Epidemiological data indicate that the risk of developing non-Hodgkin lymphoma (NHL) in HIV positive individuals is related to age and CD4 count (i.e. degree of immunosuppression). The prognosis of patients with HIV-NHL has been shown to be linked to several features including age, stage, modified IPI, prior AIDS diagnosis, CD4 count, immunoblastic pathology, LDH, and HAART use. These features are, as would be expected, a mixture of prognostic factors relating to both the HIV, and to the NHL. Population studies indicate that the incidence of associated (HIV-NHL) may be reducing with the advent of HAART, although not all studies concur. However, most population-based studies have not as yet shown a significant improvement in the survival of patients with HIV-NHL with HAART. The optimal chemotherapy for these patients is unknown, although it is generally accepted that CNS prophylaxis is mandatory. There is currently no good evidence of any survival benefit with increased dose intensity from large RCT. However, it must be borne in mind that the large randomised studies comparing differing dose intensities were undertaken before the advent of effective HAART. There is some evidence that there may be a subset of good prognosis patients who may benefit from more intensive therapy. Given that the prognosis of patients with HIV can now be considerably improved with HAART, we cannot necessarily assume that the same results would apply with regard to chemotherapy dose intensity. There is some evidence that there is a survival benefit from the addition of HAART to chemotherapy, although this is retrospective. It is likely, however, that the reason for this is that the HAART improves the prognosis of the patients from their HIV, and therefore reduces the number of patients dying from other HIV-related illnesses whilst in remission from their lymphoma, as was seen in large numbers of patients in the earlier chemotherapy trials. It must not be forgotten that the prognosis of the patient's NHL is intimately linked to their prognosis with respect to the HIV. Although the number of patients with HIV-NHL is currently few, there is a need for more trials of chemotherapy, particularly now in the HAART era, when the prognosis from the point of view of the HIV has improved so much. In particular, the issue of dose intensity needs revisiting for patients whose overall prognosis can be improved by commencing HAART. Patients with HIV-NHL should be managed at specialist centres, and where possible should be managed as part of RCT.

Anti-HIV Agents↗

PubMed1984

Determination of heparin activity by a new laser nephelometric method and comparison to the USP method.

A new method for the determination of heparin activity in solutions has been developed, based on the increase in light scattering observed during the clotting of plasma. The recalcification clotting time (RCT) of sheep plasma is measured in the presence of heparin, using a laser nephelometer. The activity of heparin in the sample is determined from a standard curve of the logarithm of RCT versus heparin activity. The results indicate that this method is simpler, faster, and more reproducible than the current USP grading method.

Animals↗

PubMed1992

Reasons for non-entry in randomized clinical trials for breast cancer: a single institutional study.

Reasons for patient non-entry in randomized clinical trials (RCTs) assessing oncologic treatment modalities are not well documented in the literature. We have prospectively recorded reasons for RCT non-entry in breast cancer patients at St. Michael's Hospital, Toronto. From September 1984 to November 1989, 592 consecutive patients were evaluated through the clinical trials office. One hundred six out of the 592 patients were placed into a RCT (17.9%). Protocol ineligibilities accounted for 273 non-entries (46.1%) and protocol eligible but not entered patients accounted for 213 (36.0%) non-entries. The most common reason for protocol ineligibility was advanced age (94 patients). The most common reason for protocol eligible but not entered patients was patient refusal (148 patients). A total of 272 patients in both non-entered groups were identified as having reasons for non-entry that were potentially correctable. In summary, protocol ineligibilities account for the majority of non-entered patients, but patient refusal accounted for the single largest group of potentially correctable non-entries. More dissemination about the merit of RCTs in the lay press and amongst primary care physicians must take place if we are to expediently and efficiently answer important oncologic questions.

Breast Neoplasms↗

PubMed2007

Context is everything: Mining the normal and preneoplastic microenvironment for insights into the diet and cancer risk conundrum.

This review highlights the context-dependence of epithelial carcinogenesis in order to illuminate the potential for progress in the field of diet and cancer prevention. Estimates drawn from observational epidemiology imply that diet and lifestyle changes have the potential to prevent 30-40% of cancer cases. However, the application of knowledge gleaned from observational epidemiology applied to randomized clinical trials (RCT) has yielded equivocal or negative results. Resolving this conundrum requires: (i) advances in diet assessment methodologies and the design of clinical trials; (ii) greater knowledge of the active components within foods which may impact cancer risk; and (iii) knowledge about the effects of dietary components on susceptible tissues throughout the disease process (Meyskens, F. L., Jr., Szabo, E., Diet and cancer: The disconnect between epidemiology and RCT. Cancer Epidemiol. Biomarkers Prev. 2005, 14, 1366-1369). Explicit consideration of the causal criteria will pay tangible benefits in the design of basic, clinical, and epidemiologic studies in cancer prevention. The rational identification of diet-dependent physiologic targets for cancer prevention is best pursued by appreciating context-dependence of epithelial carcinogenesis. Five contexts, or paradigms useful in understanding the multifactorial nature of carcinogenesis, are offered which describe the potential diet-associated physiologic influences on normal and preneoplastic cells and tumor microenvironments. Taken together with the interactions of systemic, endocrine, and autocrine/paracrine signals that may modulate the process of carcinogenesis, we can appreciate how dietary factors may act collectively in normal tissues or at early stages of carcinogenesis to prevent cancer. Only by understanding the effect of dietary components on the cellular and stromal components of the tissue microenvironment early in the process of epithelial carcinogenesis will yield clues useful for the development of improved strategies for cancer prevention.

Diet↗

PubMed2005

"Unblinding" in randomized controlled drug trials for urinary incontinence: Implications for assessing outcomes when adverse effects are evident.

AIMS: To determine whether women with urinary incontinence (UI) can identify their allocation in a randomized controlled trial (RCT) of tolterodine (TOL), and whether correct identification is associated with outcomes and adverse effects (AEs). METHODS: Exploratory analysis of a randomized, double-blind, placebo (PLC)-controlled trial of TOL 4 mg daily for 8 weeks in 743 women with urge-predominant mixed UI. Patient perception of their randomization was assessed at trial end. Main outcome measures were 7-day bladder diaries, patient perception of improvement, and UI-specific quality of life (QoL). RESULTS: TOL produced a significant decrease in urge UI episodes compared to PLC (78% vs. 51%, P = 0.0001). Fifty-one percent of women correctly identified their randomization (58% on TOL vs. 37% on PLC, P < 0.001). Women who assumed they took TOL had better bladder diary outcomes than those who assumed they took PLC. Within each assumption group, patient perception outcomes were similar, regardless of actual randomization. QoL improved in all domains except general health for women on TOL. In women who assumed they took TOL, significant drug benefit was evident in three domains. Moderate-severe dry mouth was higher in those who assumed they took TOL (7.3% vs. 0%, P < 0.0001). CONCLUSIONS: Greater than fifty percent of women in this RCT of antimuscarinic treatment were "unblinded" to their randomization. Patient assumption of randomization was associated with bladder diary and perception outcomes, specific QoL domains, and dry mouth. Efficacy of urge incontinence drugs should be considered in the context of patient assumptions, expectations, and "unblinding" by easily evident side effects.

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PubMed2001

Copper-associated liver disease in North Ronaldsay sheep: a possible animal model for non-Wilsonian hepatic copper toxicosis of infancy and childhood.

Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis (ETIC) and idiopathic copper toxicosis (ICT), are clinically and pathologically indistinguishable liver disorders of infants and young children linked with exogenous copper and with increasing evidence for a genetic predisposition. North Ronaldsay sheep are a primitive breed which have adapted to a copper impoverished environment (<5 ppm) and display an abnormal sensitivity to copper poisoning when transferred to a copper replete (11 ppm) habitat. The aetiological parallels prompted a study of copper-associated liver disease in North Ronaldsay sheep (RCT) to see if the pathology could contribute to the understanding of the childhood disorder. A retrospective study was performed in which the livers of 22 mainland-bred North Ronaldsay sheep were compared with three island-bred sheep and categorized for liver copper content and pathomorphology. It was found that all the mainland sheep had accumulated liver copper (>300 microg/g), in contrast to the island sheep, although 10 sheep with increased liver copper (mean 600 SD 270 microg/g) showed no evidence of liver damage. A further 10 sheep with liver copper (mean 1276 SD 508 microg/g) exhibited periportal to panlobular histochemical copper retention, a periportal and/or panlobular pericellular fibrosis, a mixed inflammatory infiltrate and cholangioplasia. Steatosis was absent and regeneration was in abeyance. Finally, two sheep (liver copper >2000 microg/g) had a more active hepatitis with a florid pericellular, panlobular fibrosis and cirrhosis. Electron microscopy identified large numbers of collagen-producing hepatic stellate (Ito) cells in periportal regions. The pathological findings were sufficiently reminiscent of ICC, ETIC and ICT to warrant further exploration of RCT as a putative animal model. The North Ronaldsay sheep liver may be a useful tool for the investigation of copper-induced fibrogenesis.

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