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PubMed2005

Final report of the early vs. late infantile strabismus surgery study (ELISSS), a controlled, prospective, multicenter study.

BACKGROUND: The optimal age for surgery for infantile esotropia is controversial. Proponents of early surgery believe that further loss of binocular vision can be prevented by early surgery, a minority believes that binocular vision can even be restored by early surgery. The ELISSS compared early with late surgery in a prospective, controlled, non-randomized, multicenter trial. METHODS: Fifty-eight clinics recruited children aged 6-18 months for the study. Each clinic operated all eligible children either 'early', i.e. at age 6-24 months, or 'late', i.e. at age 32-60 months. At baseline the angle of strabismus, refraction, degree of amblyopia and limitation of abduction were assessed. Intermediate examinations took place every six months. Children were evaluated at age six in the presence of independent observers. Primary endpoints were (i) level of binocular vision, (ii) manifest angle of strabismus at distance and (iii) remaining amblyopia. Secondary endpoints were number of operations, vertical strabismus, angle at near and the influence of surgical technique. RESULTS: A total of 231 children were recruited for early and 301 for late surgery. Age at entry examination was 11.1 months (SD 3.7 months) in the early group and 10.9 (SD 3.7) months in the late group. Refraction, amblyopia and limitation of abduction were distributed equally in the early and late groups, but the angle of strabismus was slightly larger in the early group. Dropout-rates were 26.0% in the early and 22.3% in the late group. At age six, 13.5% of the early vs. 3.9% of the late group recognized the Titmus Housefly; 3.0% of the early and 3.9% of the late group had stereopsis beyond Titmus Housefly. No significant difference was found for angle of strabismus. 35.1% of the early group and 34.8% of the late group did not have an angle between 0 degrees and 10 degrees , the thresholds set for re-operation. For ratio of the visual acuities (remaining amblyopia) there was a small but significant advantage for the early group. There was hardly any correlation between the baseline parameters and the primary endpoints. Children scheduled for early surgery had first been operated at 20 (SD 8.4) months, but 8.2% had not been operated at age six. Children scheduled for late surgery had been operated at 49.1 (SD 12.7) months, but 20.1% had not been operated at age six. The number of operations per child was 1.18 (SD 0.67) in the early and 0.99 (SD 0.64) in the late group. Age at recruitment, age that strabismus reportedly had started and refraction at entry examination were similar among operated and non-operated children. Only the angle of strabismus at entry predicted, to some extent, whether a child had been operated at age six. DISCUSSION: Children operated early had better gross stereopsis at age six as compared to children operated late. They had been operated more frequently, however, and a substantial number of children in both groups had not been operated at all.

Depth Perception↗

PubMed2004

Diagnostic occlusion test in cases of unilateral strabismus sursoadductorius.

PURPOSE: To investigate the diagnostic occlusion test (OT) according to Marlow in strabismus sursoadductorius (StS; also known as 'unilateral superior oblique palsy') and its implications for surgical treatment. METHODS: In 67 cases of StS, angles of strabismus were measured before and after patching the affected eye for three days. Horizontal, vertical and torsional deviations were measured in front of the tangent screen of Harms in nine directions of gaze. RESULTS: After OT, most cases of StS showed the following distribution of vertical deviation (VD) on horizontal versions: setting the VD in 30 degrees adduction to 100%, VD in primary position (PP) was 50%, VD in abduction 14%, excyclotropia in PP about 40% of the amount of VD. Those StS-cases showing the same distribution of VD on horizontal versions before and after OT were called 'typical' ones (27% of the patients). However, 73% of the patients showed a different distribution before OT: 68% VD in PP, 36% VD in abduction, excyclotropia of 20% in PP. After OT these cases converted to the normal pattern described above: VD in PP was 53 % and VD in 30 degrees abduction was 19%, excyclotropia in PP was 36%. CONCLUSION: In 'typical' StS-cases, OT is not necessary. 'Atypical' cases, however, can be converted into 'typical' ones: they get more incomitant VD on horizontal versions and greater excyclotropia in PP. As VD in adduction remains almost the same in both groups after OT, surgery can be based on the angle in adduction. In individual 'atypical' patients the amount of oblique muscle surgery has to be modified after OT.

Diagnostic Techniques, Ophthalmological↗

PubMed2004

Micrometastatic bone marrow cells at diagnosis have no impact on survival of primary breast cancer patients with extensive axillary lymph node involvement treated with stem cell-supported high-dose chemotherapy.

BACKGROUND: To determine the impact of micrometastatic bone marrow cells (MMC) on survival in high-risk primary breast cancer (HRPBC) patients treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). PATIENTS AND METHODS: Ninety-one HRPBC patients (73 patients with > or =10 involved axillary lymph nodes (ALN), 18 premenopausal women with > or =4 involved ALN) received one cycle (eight patients) or two cycles of HDCT and ASCT. Bone marrow aspiration was performed before systemic treatment to search for MMC using a cocktail of four monoclonal epithelial-specific antibodies (5D3, HEA125, BM7 and BM8). The influence of MMC and other prognostic factors on disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) was analysed. RESULTS: In 23 of 91 patients (25%) we detected a median of three MMC (range, 1-43) among 10(6) mononuclear cells. With a median follow-up of 62 months (range, 10-117), the detection of MMC was not associated with DFS (P=0.929), DDFS (P=0.664) or OS (P=0.642). In multivariate analysis the strongest predictor was nodal ratio for DFS (P=0.012) and expression of p53 for OS (P <0.001). CONCLUSION: The detection of MMC at diagnosis has no impact on survival in HRPBC patients treated with HDCT and ASCT.

Adult↗

PubMed2004

Acupuncture compared to placebo-acupuncture for postoperative nausea and vomiting prophylaxis: a randomised placebo-controlled patient and observer blind trial.

This randomised, placebo-controlled, patient and observer blinded trial was conducted to determine whether acupuncture at the acupuncture point P6 is effective in preventing postoperative nausea and vomiting (PONV) compared to placebo acupuncture. Female patients (n = 220) scheduled for gynaecological or breast surgery were randomly assigned to two groups receiving either acupuncture (n = 109) or placebo acupuncture (n = 111). Each group was stratified for type of surgery and included two subgroups receiving intervention either before or after induction of anaesthesia. The incidence of PONV and/or antiemetic rescue medication within 24 h after surgery was the main outcome measure which showed no statistically significant difference between groups (43.7% acupuncture, 50.9% placebo, p = 0.27). The differences were more pronounced for patients having gynaecological surgery (48.9% acupuncture, 67.6% placebo, p = 0.07) than for those having breast surgery (38.7% acupuncture, 40.3% placebo, p = 0.86). The secondary outcome, vomiting, was significantly reduced by acupuncture from 39.6% to 24.8% (p = 0.03). Subgroup analysis showed no difference between applications of acupuncture before compared to after induction of anaesthesia.

Acupuncture Therapy↗

PubMed2003

[Incidence and extent of postoperative macular edema following vitreoretinal surgery with and without combined cataract operation].

PURPOSE: In the majority of patients with full-thickness macular hole, closure can be achieved with vitreoretinal surgery techniques. However, postoperative function is variable and the prognostic determinants for visual acuity are incompletely understood. We evaluated the incidence and extent of macular edema after macular foramen surgery with and without combined cataract-surgery. METHODS: Between October 1997 and March 2001 macular foramen surgery was performed in 125 eyes from 116 patients. Fluorescein angiograms with sufficient quality were obtained from 59 eyes using a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph, HRA, Heidelberg Engineering, Heidelberg) and were evaluated by two independent observers. RESULTS: Angiographic macular edema was noted on average 4.2 months after the operation in 47 out of 59 (79.7%) eyes. The incidence of macular edema was 87% in eyes after a combined cataract operation compared to 66.7 % in eyes with no simultaneous operation ( p=0.735). Mean postoperative visual acuity was 0.4 (min 0.1-max 1.2) with no significant difference between eyes with (4.1 lines) and without macular edema (3.5 lines) with regard to visual improvement from baseline. CONCLUSIONS: The results indicate a high incidence of macular edema in eyes after macular hole surgery with subsequent anatomical success. Apparently, the presence of macular edema is not associated with short term visual impairment. Furthermore it seems that a combined cataract operation compared to a consecutive procedure is not associated with disadvantages regarding the functional outcome.

Aged↗

PubMed2003

Digital analysis of choroidal neovascularisation in consecutive fluorescein angiograms for use in longitudinal clinical trials.

BACKGROUND/AIMS: To document the natural history and to assess the efficacy of interventional therapies in neovascular age related macular degeneration (AMD), an accurate and reproducible method is required for analysis of consecutive fluorescence angiograms. The development and evaluation of an image analysis software for this purpose is described here. It allows for the quantitative analysis of changes in CNV and/or leakage area over time. METHODS: In digitised angiograms, a mouse driven arrow was used to delineate the CNV border. The ratio of the CNV area to the square of the distance between two vessels was automatically calculated by pixel count to compensate for variation in image sizes at different examination times. These results were directly transferred and stored in a database. To assess reproducibility, CNV areas in 20 patients with occult and 20 patients with classic CNV were determined independently by two readers. RESULTS: There was only marginal variability between observers with this method: the mean deviation was 0.01 pixels for classic CNV (95% CI -0.17 to +0.15, SD 0.35) and 0.55 pixels for occult CNV (95% CI -1.06 to -0.04, SD 1.14). CONCLUSIONS: This practical PC based method allows for quantification of angiographic features such as CNV size in early frames and area of leakage in late frames. Limitations include non-readily defined borders in angiograms of poor image quality or indistinct borders of the hyperfluorescent areas of interest. The software is applicable to future clinical trials where the analysis of neovascular complex changes is required, for example, following therapeutic intervention.

Choroidal Neovascularization↗

PubMed2001

Intention-to-treat: methods for dealing with missing values in clinical trials of progressively deteriorating diseases.

Since it came up in the 1960s, the principle of intention-to-treat (ITT) has become widely accepted for the analysis of controlled clinical trials. In this context the question of how to perform such an analysis in the presence of missing information about the main endpoint is of major importance. Uncritical use of several ad hoc strategies for dealing with missing values is common in the practice of clinical trials. On the other hand, little is known about possible dangers and problems of applying these strategies. We therefore performed a detailed investigation of different methods for dealing with missing values in order to develop recommendations for their practical use. A simulation study was performed investigating possible consequences on type I error and power of applying different methods for dealing with missing values. The simulations were based on a clinical trial of osteoporosis, a progressively deteriorating disease. The strategies examined can be roughly classified into numerical imputation strategies (last observation carried forward, mean and regression based methods) and non-parametric strategies (rank and dichotomization based methods). Different drop-out mechanisms and different types of progression of disease are considered. The type I error increases drastically for the different strategies, especially if the courses of disease vary between treatment groups. The loss in power can be substantial. There is no strategy which is adequate for all different combinations of drop-out mechanisms, drop-out rates and courses of disease over time. For drop-out rates less than 20 per cent and similar courses of disease in the treatment groups, missing values might be replaced by the mean of the other group, or counted as treatment failures after dichotomization of the endpoint. For larger drop-out rates or less similar courses of disease, no adequate recommendations can be given. Because of the drastic consequences of increasing drop-out rates, it has to be a primary goal in clinical trials to keep missing values to a minimum. Unobserved information cannot be reliably regained by any methodological resources. As there are no strategies for universal use, reasons for the choice of a certain method have to be provided when designing and analysing clinical trials.

Computer Simulation↗

PubMed2001

Prognostic value of Doppler echocardiographic mitral inflow patterns: implications for risk stratification in patients with chronic congestive heart failure.

OBJECTIVES: This prospective study tested whether transmitral flow patterns add incremental value to peak oxygen consumption (VO2) in determining the prognosis of patients with chronic congestive heart failure (CHF) and systolic dysfunction. BACKGROUND: Peak VO2 is an objective marker of functional capacity and is routinely used as a criterion to identify heart transplant candidates. Diastolic dysfunction limits functional capacity, but its prognostic importance relative to that of peak VO2 is unknown. METHODS: Peak VO2 and mitral inflow velocities were prospectively measured in 311 consecutive patients (mean age 54 years, 84% male) with impaired left ventricular function (ejection fraction <40%; 88 patients with ischemic and 223 with dilated cardiomyopathy) who were evaluated for heart transplant candidacy. RESULTS: During a mean follow-up period of 512 +/- 314 days, 65 patients died and 43 patients underwent heart transplantation. Diastolic filling patterns, peak VO2 and left ventricular end-diastolic diameters were independent predictors of cardiac mortality. In patients with peak VO2 < or = 14 ml/min per kg body weight, the outcome was markedly poorer in the presence of restrictive filling patterns as compared with their absence (two-year survival rate 52% vs. 80%). Similarly, despite peak VO2 levels >14 ml/min per kg, the outcome was less favorable in the presence of restrictive filling patterns (two-year survival rate 80% vs. 94%). A risk-stratification model based on the identified independent noninvasive predictors separated groups into those with high (93%), intermediate (65%) and low (39%) two-year survival rates. CONCLUSIONS: Transmitral flow patterns add incremental value to peak VO2 in determining the prognosis of patients with CHF and impaired systolic function.

Blood Flow Velocity↗

PubMed2000

Nonconvulsive status epilepticus--a possible cause of mental retardation in patients with Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome (LGS) is one of the most severe types of childhood epilepsy. It is usually resistant to treatment and associated with mental retardation. To delineate the risk factors associated with the outcome of LGS, we evaluated, in a retrospective and multicentre study, the course of the disease, EEG tracings, and intellectual function in 101 patients. Inclusion criteria were the presence of tonic seizures as well as slow spike and wave complexes in the EEG. The average documented observation period was 16 years (range 4-31 years). Overall, the intellectual and neurological outcome was poor. At the last follow-up, 38% of the patients could not speak, 21% were unable to walk and only 4% were free of seizures. Four independent risk factors for severe mental retardation were identified by multivariate analysis. These were in a decreasing order of importance: nonconvulsive status epilepticus (NCSE), odds ratio (OR) 25.2, a previous diagnosis of West syndrome (OR 11.6), a symptomatic etiology of epilepsy (OR 9.5), and an early age at onset of epilepsy (OR 4.7). The results highlight the association between NCSE and the severity of mental retardation in patients with LGS; this association appears to be independent of symptomatic etiology. Our data provide an indirect evidence that, at least in some of the patients, NCSE is not only a concomitant feature, but also a cause of severe mental retardation.

Adolescent↗

PubMed2000

[Basic principles of clinical therapeutic studies--what, how and why?].

Treatment evaluation is one of the most important tasks in medical research. Detailed standards have been developed during the last decades. The efficacy/effectiveness of treatments can only be assessed in comparison to control groups. To guarantee the internal validity of these comparisons, the groups have to be comparable at the beginning of the study. This can be achieved by randomized allocation of patients to treatment. Furthermore, as far as possible patient and physician should be blinded to treatment in order to avoid subjective influences on treatment results. Groups should still be comparable when analysing the trial, thus an analysis according to the principle of intention-to-treat ("as randomized") should be performed. These indispensable principles for design, conduct and analysis of clinical trials are widely accepted and contribute to reliable and credible results.

Humans↗

PubMed2000

[Monitoring clinical studies. Development, measures and consequences].

BACKGROUND: Clinical trials play an important role in developing and establishing new therapeutic and diagnostic procedures. In the planning and execution of these trials procedures and measures which allow for continual observation, description and evaluation of the study progress are to be taken into account. This is due to ethical, scientific and economic considerations. Together these procedures and measures are termed "monitoring". Repeated evaluation of the main study question is one particular monitoring measure. Results from this sequential procedure may lead to an early termination of patient recruitment. In the last 3 decades methods for interim analyses were developed which take into account the increased chance of errors when evaluating repeatedly the same question. By adjustment they guarantee a prespecified level of significance in the end result of the trial. Even though statistical significance may be evident in an interim analysis, this has not always to result in early termination of the trial. The decision to end a trial early must include other considerations than the mere evaluation of the main study question. In particular, consequences of the decision such as credibility and transferability of the trial result to subsequent therapeutic routine application are to be discussed.

Clinical Trials as Topic↗

PubMed1999

[Monitoring of clinical trials. Methodology, interim analyses, and end results].

BACKGROUND: Clinical trials play an important role in developing and establishing new therapeutic and diagnostic procedures. In the planning and execution of these trials procedures and measures which allow for continual observation, description and evaluation of the study progress are to be taken into account. This is due to ethical, scientific and economic considerations. Together these procedures and measures are termed "monitoring". Repeated evaluation of the main study question is one particular monitoring measure. Results from this sequential procedure may lead to an early termination of patient recruitment. In the last 3 decades methods for interim analyses were developed which take into account the increased chance of errors when evaluating repeatedly the same question. By adjustment they guarantee a prespecified level of significance in the end result of the trial. Even though statistical significance may be evident in an interim analysis, this has not always to result in early termination of the trial. The decision to end a trial early must include other considerations than the mere evaluation of the main study question. In particular, consequences of the decision such as credibility and transferability of the trial result to subsequent therapeutic routine application are to be discussed.

Clinical Trials as Topic↗

PubMed1999

[Basic principles of clinical trials--what, how, and why?].

Treatment evaluation is one of the most important tasks in medical research. Detailed standards have been developed during the last decades. The efficacy/effectiveness of treatments can only be assessed in comparison to control groups. To guarantee the internal validity of these comparisons, the groups have to be comparable at the beginning of the study. This can be achieved by randomized allocation of patients to treatment. Furthermore, as far as possible patient and physician should be blinded to treatment in order to avoid subjective influences on treatment results. Groups should still be comparable when analysing the trial, thus an analysis according to the principle of intention-to-treat ("as randomized") should be performed. These indispensable principles for design, conduct and analysis of clinical trials are widely accepted and contribute to reliable and credible results.

Clinical Trials as Topic↗