Independence estimating equations for controlled clinical trials with small sample sizes--interval estimation.

OBJECTIVES: The application of independence estimating equations (IEE) for controlled clinical trials (CCTs) has recently been discussed, and recommendations for its use have been derived for testing hypotheses. The robust estimator of variance has been shown to be liberal for small sample sizes. Therefore a series of modifications has been proposed. In this paper we systematically compare confidence intervals (CIs) proposed in the literature for situations that are common in CCTs. METHODS: Using Monte-Carlo simulation studies, we compared the coverage probabilities of CIs and non-convergence probabilities for the parameters of the mean structure for small samples using modifications of the variance estimator proposed by Mancl and de Rouen [7], Morel et al. [8] and Pan [3]. RESULTS: None of the proposed modifications behave well in each investigated situation. For parallel group designs with repeated measurements and binary response the method proposed by Pan maintains the nominal level. We observed non-convergence of the IEE algorithm in up to 10% of the replicates depending on response probabilities in the treatment groups. For comparing slopes with continuous responses, the approach of Morel et al. can be recommended. CONCLUSIONS: Results of non-convergence probabilities show that IEE should not be used in parallel group designs with binary endpoints and response probabilities close to 0 or 1. Modifications of the robust variance estimator should be used for sample sizes up to 100 clusters for CI estimation.

Survival in hereditary breast cancer associated with germline mutations of BRCA2.

PURPOSE: Breast cancer in BRCA1 and BRCA2 gene-mutation carriers may differ from so-called sporadic breast cancer in clinical features and behavior. These potential differences may be of importance for the prevention, screening, and, ultimately, treatment of breast cancer in women with such germline mutations. Thus far, there have been very few studies on the survival of BRCA2-associated breast cancer patients. PATIENTS AND METHODS: We determined the disease-free and overall survival of 28 breast cancer patients from 14 consecutive families with eight different BRCA2 germline mutations. These patients' survival and tumor characteristics were compared with those of a control group of 112 sporadic breast cancer patients matched to them by age and year of diagnosis. RESULTS: The 5-year disease-free survival was 52% for each group (P =.91); the overall survival was 74% for BRCA2 carriers and 75% for sporadic cases (P =.50). At the time of diagnosis, tumors from the BRCA2 carriers were borderline significantly larger in comparison to the tumors in sporadic cases (P =.05), but axillary nodal status was not significantly different in the two groups (node-negativity, 63% v 52. 8%, respectively; P =.34). With respect to steroid receptor status, BRCA2-associated tumors were more likely to be steroid receptor-positive, especially regarding progesterone receptor status (100% v 76.7% positive, respectively; P =.06). Stage-adjusted recurrence and death rates were nonsignificantly better for BRCA2 cases (hazard ratios of 0.84 and 0.59 [P =.61 and P =.19], respectively). In contrast, after 5 years, the rate of metachronous contralateral breast cancer in BRCA2 patients was 12% (v 2% in controls; P =.02). CONCLUSION: Patients with hereditary breast cancer due to BRCA2 have a similar prognosis when compared with age-matched sporadic breast cancer patients. Contrary to our previous observation regarding BRCA1-associated breast cancer, BRCA2 tumors tended to be steroid receptor-positive, instead of steroid receptor-negative.

Intra-articular empyema due to Staphylococcus caprae following arthroscopic cruciate ligament repair.

Staphylococcus caprae is a catalase-positive, coagulase-negative coccus that has been originally isolated from goat milk. We describe the first case of an intra-articular empyema caused by S. caprae in an immunocompetent patient following arthroscopic cruciate ligament repair. The patient recovered completely after debridement and antibiotic therapy with cefazolin and amoxicillin, respectively. This case demonstrates that this organism may rarely cause serious nosocomial infections in immunocompetent adults.

Sample size calculations for controlled clinical trials using generalized estimating equations (GEE).

OBJECTIVES: Clinical trials with correlated response data based on generalized estimating equations (GEE) have become increasingly popular as they require smaller samples than classical methods that ignore the clustered nature of the data. We have recently derived the recommendation to use the independence estimating equations (IEE) as primary analysis in most controlled clinical trials instead of GEE with estimated correlations. Although several approaches for sample size and power calculation have been proposed, we have shown that most of these procedures are very specific and not as general as required for designing clinical trials. METHODS: We extended the previously developed SAS macro GEESIZE to overcome this restriction. Specifically, we have added the option of an independence working correlation matrix required for the IEE. Additionally, we have reformulated the hypotheses to allow for coding that includes an intercept term instead of the previously used analysis of variance coding. RESULTS: To demonstrate the validity of GEESIZE we investigate the calculated sample sizes for specific models where closed formulae are available. For illustration, we utilize GEESIZE for planning a new trial on the treatment of hypertension and thereby exemplify its flexibility. CONCLUSIONS: We show that our freely available macro is a very general and useful tool for sample size calculation purposes in clinical trials with correlated data.

[Present state of radio frequency ablation of liver tumors in Germany]. / Aktueller Stand der Radiofrequenzablation von Lebertumoren. Eine deutschlandweite Umfrage.

INTRODUCTION: Radio frequency ablation (RFA) represents a new technique for local destruction of liver tumors. Indication and procedure are poorly validated at present. METHOD: To record the actual nationwide RFA application in Germany, a survey of 2026 hospitals with standardized questionnaires was conducted. RESULTS: With a respond rate of 17.5%, results from 58 hospitals covering 1700 ablated patients were analyzed. In 25.9% of them, RFA is already used in potentially curative resectable tumors, in 22.4% even when incomplete ablation for tumor mass reduction is expected. Of the 58 hospitals, 75% combine resection and RFA to reach a so-called R-0 situation. The maximal tumor sizes they quoted for achieving complete ablation ranged from <3 cm to 11 cm. In contraindications for RFA, the tumor size, number of tumors, critical localization of the tumor, and disorders of liver function were mentioned the most. CONCLUSION: This survey documents significant discrepancies in indication, application, procedure, and results in RFA for liver tumors. The lack of general standards and an overestimation of the method may lead to uncritical application, neglect of standard therapy, or unsatisfying results.

[Involvement of the inner malleolus and deltoid ligament in supination trauma of the ankle joint]. / Die Beteiligung des Innenknöchels und des Ligamentum deltoideum beim Supinationstrauma des Sprunggelenkes.

Additional ligament ruptures or fractures of the medial side of the ankle joint accompanying the lateral ligament rupture are rare. These injuries are more often in traumas with pronation-eversion movements of the foot. In cases of lateral ligaments ruptures we only found in 2.8% and in 5.9% additional medial injuries. This is confirmed by different biomechanical experiments. Experimentally the delta ligament rupture could mostly be caused by pronation-eversion movements or by forced plantar flexion of the foot. The diagnosis of bony lesions of the medial malleolus might be easy by X-ray, but ligament lesions of the medial ankle joint can be diagnosed easily too be using the stress X-ray controlling the medial talar tilt as a sign of medial instability. Because the necessity of surgical treatment is less important than of the lateral ligaments we recommend this procedure in cases of bilateral instability or if dislocation is obvious.

[The "positioned image" of the talo-calcaneus joint in instability of the posterior distal ankle joint]. / Die "gehaltene Aufnahme" des Talo-Calcanear-Gelenkes bei Instabilitäten des hinteren unteren Sprunggelenkes.

With regard to the very common disease of sprained ankles the combined tear with ruptures of ligaments of the subtalar joint are possible. Even an isolated instability is known as the reason of long lasting post-traumatic complaints. Using the apparatus of Scheuba, well-known in diagnosing instabilities of the knee and ankle joint, a new standardized method controlling instabilities of the subtalar talo-calcanear joint is introduced. In an experimental investigation this radiological technique has been tested out in cadaveric ankle joints (nine joints) with artificial ligamentous lesions. The results show that in all cases an instability is recognizable radiologically using this technique. For clinical use the bilateral examination is recommended failing standardized values for unilateral use.

Dilution of dye improves parametrial SLN detection in patients with cervical cancer.

OBJECTIVE: Aim of this study to improve the detection rate of parametrial sentinel nodes in patients with early cervical cancer by using a new dosage of blue dye in a randomized trial. METHODS: Standard labelling volume of 4 ml Patent Blue was compared to 2 ml Patent Blue diluted with 8 ml NaCl 0.9% in 60 patients using a randomized protocol. Tc-99 was not applied in any patient. All patients underwent open lymphadenectomy. RESULTS: In each arm 30 patients were enrolled. Overall detection rate of sentinel nodes was 93.3%. Both groups did not differ with regard to patient's age, BMI, tumor stage, number of lymph nodes harvested, number of sentinel nodes detected and detection rate. Significantly more patients with parametrial sentinel nodes were detected in the diluted protocol (37.0% vs. 10.3%) which is due to the lateral part of the cardinal ligament (29.6% vs. 6.9%). CONCLUSION: In our study overall detection of sentinel nodes using a dye was high. The diluted solution of Patent Blue led to a higher detection rate of parametrial sentinel nodes. These findings might help explain the discrepancy between the high reported rate of parametrial lymph nodes in anatomical studies compared with the low rates in clinical sentinel series.

Echocardiographic and hemodynamic characteristics of reconstructed bicuspid aortic valves at rest and exercise.

Repair of diseased bicuspid aortic valves has gained increasing interest as an alternative to conventional valve replacement. Hemodynamic data at exercise have not been reported before. The aim of this study was to investigate the clinical and echocardiographic status of patients after bicuspid aortic valve repair at rest and exercise. Between 03/94 and 09/02 a reconstruction of an incompetent bicuspid aortic valve was performed in 25 patients (mean age 35+/-12.1 years, group A, mean insufficiency 2.8 preoperatively). Patients were investigated clinically and echocardiographically after 2.1+/-2.4 (0.1-8.9) years at rest and exercise and compared to 20 controls (group B). Clinical followup was complete. There were no deaths, reoperations, thromboembolic or bleeding complications. At last examination 21 patients were in NYHA class I, n=4 in NYHA class II and mean aortic valve insufficiency (AI) was 1.0 with one patient having an AI>II degrees. Maximum and mean pressure gradient (dPmax/mean) across the aortic valve at rest were 14+/-5.5/7+/-2.6 mmHg for patients of group A and 7+/-2.5/3.6+/-1.1 mmHg in group B. Mean AVA at rest was 2.6+/-0.8 (group A) vs 2.9+/-0.6 cm(2) (group B, p=0.025), valvular resistance 13.4+/-4.8 (group A) vs 13.6+/-2.9 dyn x s x cm(-5) (group B, p>0.05). All individuals were stressed up to 100 W (dPmax/mean 21+/-6.8/11+/-3.6, group A vs 11+/-2.9/6+/-1.3 mmHg, group B). 56% of group A and 85% of group B could be stressed up to 175 W with dPmax/mean 24.5+/-8.3/12+/-4.2 and 16+/-3.6/8+/-1.4 mmHg, respectively (p<0. 01). Heart rate and blood pressure behavior were comparable. Left ventricular mass regression (preoperatively 369.3+/-76.4 vs 277.3+/-80.7 g at last examination, p<0.01) was significant in group A but did not reach normal values (group B, 227.8+/-71.1; p<0.01). Bicuspid aortic valve reconstruction reduces left ventricular volume load significantly. Although residual mild subclinical obstruction and incompetence were observed, the behavior of hemodynamics at exercise was comparable to controls. The clinical relevance of these findings in long term follow-up has to be evaluated.

[Orthopedic diseases in children and adolescents--indications for prohibiting sports participation]. / Orthopädische Krankheiten im Kindes- und Jugendalter--Indikation zum Sportverbot.

School sports is not only a compensation for inactivity but also training and basic experience in many kinds of sports. The stress exercised by school sports is similar to that of hobby sports. The dimension of errors in respect of excessive stress in orthopaedic diseases and the biological development--acceleration/retardation--is important for prohibiting school sports in some diseases. The indication for prohibiting school sports either completely or incompletely in the most important orthopaedic diseases in childhood, is discussed. The special importance of part prohibition or participation without any giving marks, is emphasised.

[Postoperative performance of the proximal femoral epiphysis after surgical treatment in epiphyseolysis capitis femoris (author's transl)]. / Das postoperative Verhalten der proximalen Femurepiphyse nach der operativen Behandlung bei der Epiphyseolysis capitis femoris.

The article reports on the performance of the proximal femoral epiphysis after isolated screw fixation, Imhäuser-Weber's operation and open repositioning with subcapital osteotomy. The indication for the choice of the operation is explained. Results of the three operative treatment methods are discussed in respect of postoperative mobility, osseous fusion period and complications. Detailed attention is paid to the localisation of the first signs of ossification.

[Long-term experience with the myoelectrical arm prosthesis for blind hand-amputees]. / Langzeiterfahrung mit der myoelektrischen Armprothese bei blinden Ohnhändern.

In the framework of a personal investigation seven blind hand amputees (survivors of world war II, and of the Portuguese colonial war) had been interviewed to study the influence of myoelectric prosthetic fitting on their social and vocational rehabilitation. Five of them use their prostheses from eight to fifteen hours a day, primarily in the office; at home they prefer their Krukenberg stump. For the clients' self-esteem, the cosmetic factors seems to be decisive. Yet all of the clients engaged in (desk) work emphasize that they could do their jobs without using the myoelectric prostheses, without however wishing to be provided with some other type of prosthesis.

[Comments on the lateral load capacity of the phalangeal joints (author's transl)]. / Uber die seitliche Belastbarkeit der Fingergelenke.

The article compares the load capacity of the collateral ligaments of the metacarpo-phalangeal and interphalangeal joints exposed to a laterally applied force. The tests were performed in vivo with 50 each female and male volunteers. It was found that the average load capacity of the metacarpo-phalangeal and interphalangeal joints in women was 5.8 kp and in men 12.3 kp. Furthermore, the bones of the long fingers with the preserved joint capsules and collateral ligaments of ten corpses were also examined, and the collateral ligaments exposed to a load which was increased to the point of their destruction. The average values found in this manner were 26.5 kp for the metacarpo-phalangeal collateral ligaments and 15.4 kp for the interphalangeal collateral ligaments. This means that the pain threshold is usually below the destruction limit, so that generally there will be no spontaneous overloading. It is important for the construction of endoprostheses that their stability level should always be above that of the pain threshold and should attain at least the values of the tear tests, since otherwise these endoprotheses will not function properly. These basic prerequisites enable a comparative study of endoprostheses, the results of which will be presented at a later date.

The gluteal approach to the ischium.

This paper describes a gluteal approach to the ischium which facilitates a good exposure of the whole region from the lower part of the ischium to the pubic ramus and allows extensive resections and partial hip reconstruction if necessary. The approach is demonstrated as used in two cases - one benign (desmoplastic fibroma) and one malignant tumor (chondrosarcoma).

[Paraplegia in manual therapy. A case report]. / Paraplegie bei Manualtherapie. Ein Fallbericht.

A case of complete paraplegia due to a giant cell tumor of the dorsal spine following manual therapy without previous x-ray examination is reported. In a malpractice trial the question whether manual therapy is indicated or not had strictly to be denied. The question whether paraplegia due to a giant cell tumor could have been avoided when the tumor would have been detected radiologically was impossible to answer retrospectively. But, it is likely that with immediate surgical therapy after radiological detection of this lesions complete paraplegia should have been avoidable.

[Results of rotation osteotomy using the Weber method in the treatment of habitual shoulder dislocation]. / Ergebnisse der Drehosteotomie nach Weber bei der Behandlung der habituellen Schulterluxation.

Weber's rotational osteotomy is a surgical treatment of recurrent shoulder dislocation. While eliminating recurrence of the complaint, it attempts to regain full range of movement in the joint. Of the 39 operated patients it was possible to follow up 34 cases. The percentage of recurrent dislocation was 5.7%. The range of movement was reduced in some patients; in one by 10 degrees - 20 degrees. Otherwise there were no significant complications or post-operative complaints. The operative technique, the X-ray procedure and the pathogenesis of the original dislocation are described. Typical accompanying injuries require a particular operative method. The most common accompanying damage was normally the typical defect of the humeral head (incidence 91%). The regular overstretching of the subscapular muscle and the defect of the humeral head are considered by the operational technique introduced by Weber.

[Partial replacement of the pelvis with the hip joint and proximal femur. A possibility in tumor treatment]. / Alloplastischer Beckenteilersatz mit Hüftgelenk und proximalem Femur. Eine Möglichkeit der Tumorbehandlung.

In cases of extensive destructive osteolytic processes in the pelvis and hip region, alloplastic replacement of a part of the pelvis with a total hip replacement and, if necessary, partial replacement of the femur, can represent a therapeutic alternative to hemipelvectomy for preserving the limb in the presence of malignancies; it offers the same degree of radicality in removing the affected bone and soft tissue while preserving the bone. This applies with regard both to primary malignant growths as well as extensive isolated metastases and aseptic osteolysis following multiple total replacement procedures. The partial pelvic prostheses, produced individually on the basis of roentgenograms, are adapted to a great degree intraoperatively and fixed with screws, locknuts, and Palacos, and if possible lined with autogenous bone. Where the defects are extensive the pubic bone of the unaffected side is incorporated in the stabilization. Experience gathered so far and follow-up examinations show that all patients regain full mobility and weight-bearing ability, with almost complete lack of complaints and adequate to good motility. This is demonstrated by examples.

[Pathogen changes in bacterial bone and joint infections (osteomyelitis, spondylitis, arthritis)]. / Erregerwandel bei der bakteriellen Knochen- und Gelenkinfektion (Osteomyelitis, Spondylitis, Arthritis).

With regard to germ mutation in osteomyelitis, spondylitis, and arthritis it has been established that the frequency of Mycobacterium tuberculosis and the gram-positive pathogens (S. albus, Streptococci) has decreased in the last 20 years. To varying degrees, S. aureus and the gram-negative, aerobic organisms are the most important pathogens of bone and joint infections. Overall, there has been an increase in the frequency of infections with gram-negative, aerobic organisms. In the majority of cases the bone and joint inflammations were caused by exogenous factors, their course was chonic, and the typical localization was the lower extremity. There was a positive trend toward shorter periods of hospitalization and a shorter duration of illness.

[Perthes disease--choice of therapy with reference to psychosocial aspects]. / Morbus Perthes--Wahl der Therapieform unter Berücksichtigung psychosozialer Aspekte.

Within the scape of a comparative long-term study between conservative and operative therapy of Perthes'-disease the effort was made to estimate the dimension of the psychic and social detraction in addiction to the method of treatment by a detailed inquiry of 116 patients as well as of their accompanying parents. This happened because of the opinion, that not only the formal result should decide on the choice of therapy, but also in a justifiable dimension the way of treatment should be orientated on patients. The analysis of the anamnestic particulars showed, that also under psycho-social aspects the immediate surgical procedure has the advantage over conservative methods of treatment at Perthes' disease.