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.

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.

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.

[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.

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.

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.

Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1.

BACKGROUND: Hereditary breast cancer has been associated with mutations in the BRCA1 and BRCA2 genes and has a natural history different from sporadic breast cancer. We investigated disease-free and overall survival for patients with a proven BRCA1 alteration. METHODS: We estimated disease-free and overall survival for 49 Dutch patients from 19 consecutive families with a proven specific BRCA1 mutation and one family with strong evidence for linkage to the BRCA1 gene. We compared clinical outcome and data on tumour size, histology, axillary nodal status, contralateral breast cancer, and oestrogen-receptor and progesterone-receptor status with those of 196 patients with sporadic breast cancer, matched for age and year of diagnosis. FINDINGS: Disease-free survival for BRCA1 and sporadic patients at 5 years was 49% (95% CI 33-64) and 51% (43-59), respectively (p=0.98). Overall survival at 5 years was 63% (47-76) and 69% (62-76), respectively (p=0.88). Recurrence and death rates did not differ significantly between groups. Hazard ratios for recurrence and death among BRCA1 patients were 1.00 (0.65-1.55) and 1.04 (0.63-1.71) relative to sporadic patients (p=0.88), and these did not differ significantly after adjustment for prognostic factors. Patients with BRCA1-associated breast cancer had twice as many progesterone-receptor-negative tumours (p<0.005) and development of contralateral breast cancer was four to five times as frequent as in the sporadic group (p<0.001). INTERPRETATION: We showed that disease-free and overall survival were similar for sporadic and hereditary breast cancer in the presence of different tumour characteristics, which has implications for screening prophylactic therapy, and different treatments of hereditary breast cancer.

[Effects of extracorporeal ultrasound shockwaves on the relatively mature embryos of the teleost Oryzias latipes]. / Uber die Auswirkungen von extrakorporalen Ultraschall-Stossenwellen auf weitentwickelte Embryonen des Knochenfisches Oryzias latipes.

Exposure to low-energy ultrasound shock waves (1000 impulses at a frequency of 2/sec and an energy density of 0.08 mj/mm2; peak positive/negative pressure 16/-7 MPa; pulse duration about 10 musec) led to the following alterations in the cells and tissues of stage 35 embryos of Oryzias latipes ranked according to their extent: (1) In various tissues, especially in the trunk musculature, orthodox mitochondria were transformed into condensed (= low energy) mitochondria. (2) Nuclear envelopes and sarcoplasmatic reticulum of muscle fibres as well as endoplasmatic reticulum of epidermal ionocytes were often vesicularly dilated. (3) Muscle fibres in the trunk musculature began to separate from each other. Epidermal intercellular spaces were enlarged and increased in number. (4) Destruction of vessels and haematomas were observed in the circulatory system of the yolk sac. (5) Necroses up to total disintegration were found in various organs of the body cavity (intestine, liver, spleen). The less serious alterations (1 and 2) occurred in organs completely surrounded by other tissues. Major damages (4 and 5), however, affected only organs with free outer and inner surfaces, probably explained by cavitation and jet stream phenomena within the adjacent fluids.

Pharmacokinetics of ampicillin, sulbactam and cefotiam in patients undergoing orthopedic surgery.

As perioperative prophylaxis for major orthopedic operations 81 patients were given the fixed combination of ampicillin (1 g)/sulbactam (0.5 g) or cefotiam (2 g) as short infusions. The three beta-lactams were rapidly distributed into the different tissues and their pharmacokinetic profiles were found to be very similar. It was noteworthy that ampicillin, sulbactam and cefotiam penetrated within minutes, not only into skin, fat and muscles, but also into bone. Thus 0.25 h after starting the infusion the following mean concentrations were measured in bone: 21.8 +/- 10.5 mg/kg ampicillin, 4.9 +/- 2.2 mg/kg sulbactam and 19.4 +/- 10.6 mg/kg cefotiam. For a period of at least 2 h the concentrations measured in serum and in the different tissues affected by the operation (skin, fat, muscle, bone) were above the MICs for pathogens which are involved in postoperative wound infections. On the basis of pharmacokinetic data, ampicillin/sulbactam and cefotiam seem about equally suitable for perioperative prophylaxis in major orthopedic operations.

Internal hemipelvectomy and endoprosthetic pelvic replacement: long-term follow-up results.

We report on our experiences with internal hemipelvectomy followed by an implantation of a endoprosthetic pelvic replacement (EPR) performed in 15 patients over a period of 15 years. Our primary aim was to determine the implications for this procedure because of its high rate of complications. Due to the malignant character of the disease and the biomechanical stress on the anatomical region, the demands on the surgeon are high. The most important factor is a sufficiently wide resection of the primary tumour because most are chondrosarcomata which do not respond to other therapies. In addition, the malignant character of the tumour has the greatest influence on the long-term results. Internal hemipelvectomy and endoprosthetic pelvic replacement are accompanied by a high rate of operative and postoperative complications Nevertheless, nearly full anatomical and functional reconstruction can be obtained provided a medium level of function is accepted. Follow-up results of the remaining six still living patients were evaluated by means of three different scoring systems. All patients had only a medium score but emphasised subjective acceptance of the endoprosthetic pelvic replacement even when removal was necessary later on. Because of the lower functional outcome of alternative operative procedures such as pseudarthroses and arthrodeses and problems with the replantation of autoclaved autografts or implantation of an allograft, internal hemipelvectomy combined with endoprosthetic pelvic replacement is the treatment of choice for these specific acetabular lesions, provided a complete resection is feasible. Otherwise, an external hemipelvectomy is necessary because even alternative limb-salvaging procedures must incorporate the same complete resection of the tumour. In cases of metastatic lesions, internal hemipelvectomy and endoprosthetic pelvic replacement are indicated relatively because of the systemic character of the disease. The procedure should be considered only when resection of a solitary metastasis enables a cure and/or prolongation of life with an improved quality of life.

M1 muscarinic mechanisms regulate intestinal-phase gallbladder physiology in humans.

The contribution of muscarinic receptor subtypes to biliary control mechanisms is unclear. We investigated stimulated gallbladder function and release of associated hormones during M1-receptor blockade. Following a double-blind, randomized, crossover protocol, healthy volunteers each received placebo and telenzepine, a selective M1-receptor antagonist, as 2-h background infusion. Gallbladder contraction (by ultrasonography), bilirubin output, and release of cholecystokinin (CCK) and pancreatic polypeptide (PP) were assessed during increasing doses of endogenous (intraduodenal nutrient) and exogenous (hormonal) stimulation. All parameters were stimulated in a dose-dependent manner on placebo days. Contractile and secretory responses to low-dose caerulein (CCK analogue) were inhibited by 60-80% under telezepine, whereas high-dose (supraphysiological) stimulation overrode this effect. Similar inhibition was achieved during nutrient stimulation. CCK plasma levels rose during endogenous and exogenous stimulation but were unaffected by M1 blockade, whereas stimulated PP release was completely inhibited (> 100% decrease), reflecting suppressed vagal tone. Selective M1-receptor blockade inhibits the physiological response of the gallbladder in humans; this effect cannot be attributed to suppressed CCK release. Our findings support the hypothesis that CCK acts at the gallbladder via cholinergic nerves under physiological conditions. Viewed with our previous observations, nonselective antagonism of biliary function by atropine is primarily mediated through M1 muscarinic pathways.

M1-muscarinic mechanisms regulate interdigestive cycling of motor and secretory activity in human upper gut.

We determined the influence of M1-muscarinic pathways in modulating temporal cycling of motor and secretory activity in the fasting upper gut. Eight healthy subjects were studied on two separate days, following a double-blind, randomized protocol. Antroduodenal motility (migrating motor complex, MMC), pancreatic exocrine secretion (amylase, lipase, trypsin, chymotrypsin), and plasma levels of associated hormones [motilin, pancreatic polypeptide (PP)] were monitored for two consecutive cycles during background infusion of placebo or telenzepine, a selective M1-muscarinic receptor antagonist. On placebo days, pancreatic enzymes and hormones cycled in synchrony with motor activity, as expected. During M1 blockade, duodenal output of each enzyme was decreased by 85-90% in phase I and by > 90% in phase III. Similarly, plasma concentrations of hormones were decreased during all phases and cycling was absent. Despite the loss of these putative influences, intestinal motility continued to cycle, albeit in an altered fashion. Intermittent phase II activity was replaced by phase I quiescence, while phase III-like fronts were diminished (contraction frequency, amplitude, propagation velocity reduced 30-60%, duration not altered) but recurred at expected intervals (cycle length 105 +/- 14 min vs 109 +/- 12 in placebo). Gastric motor activity was virtually abolished. These data suggest or extend several working hypotheses: (1) Motilin is released and/or acts via cholinergic (M1-muscarinic) pathways to initiate antral, but not duodenal, phase III activity. (2) M1 receptors mediate all components of the gastric MMC and phase II activity throughout the gut, but intestinal phase III activity arises via alternate pathways. (3) M1-muscarinic mechanisms regulate interdigestive cycling of pancreatic enzymes and PP. (4) Secretions from the endocrine/exocrine pancreas are not primary mediators of intestinal motility.

[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.

Gastrointestinal motor and secretory responses to cholinergic stimulation in humans. Differential modulation by muscarinic and cholecystokinin receptor blockade.

The present study investigated how a cholinergic agonist modifies interdigestive motility and secretion of the upper gastrointestinal tract and how muscarinic and cholecystokinin receptor blockade interfere with this direct cholinergic stimulation. In eight healthy volunteers, gastrointestinal motor and secretory responses to bethanechol (12.5, 25, and 50 micrograms kg-1 h-1) with and without a background of atropine (5 micrograms kg-1 h-1) or loxiglumide (10 mg kg-1 h-1) were studied. Stepdoses of bethanechol caused a parallel stimulation of antroduodenal motility and gastropancreatic secretion (P < 0.01) without inducing a fed pattern. However, duration of phase I was shortened (P < 0.05). Only high doses of bethanechol enhanced gastrin (P < 0.05), cholecystokinin (P < 0.05), and pancreatic polypeptide (P < 0.01) release. Atropine completely antagonized motor and secretory responses to cholinergic stimulation. Loxiglumide left cholinergically stimulated motility and pancreatic enzyme secretion unaltered. With co-infusion of bethanechol and loxiglumide, PP release dropped by 63% (P < 0.01); gastric acid output, gastrin and CCK release increased by 56%, 16%, and 25%, respectively (P < 0.05). We conclude that stimulation by a cholinergic agonist preserves the interdigestive pattern. Low dose muscarinic receptor blockade abolishes cholinergic stimulation over the full dose range. Inhibition of somatostatin release would explain stimulation of gastrin release and gastric acid secretion with co-infusion of bethanechol and loxiglumide. Endogenous CCK appears to interact with direct cholinergic stimulation at the pancreatic PP cell and the gastric D-cell but not at pancreatic acinar and antroduodenal smooth muscle cells.

Morbus de Anquin or spinous engagement syndrome. A rare cause of low-back pain syndrome and sciatica.

We report on a rare disease called to Anquin's disease or spinous engagement or impingement syndrome. Low-back pain in this specific syndrome probably combined with sciatica is caused by a hypertrophic spinous process along with a spina bifida occulta of the underlying vertebra. Mostly, the enlarged spinous process is seen at L5 and the spina bifida occulta at S1. Conservative therapy consists of physiotherapy with postural exercises including improvement of lumbar flexion. If conservative treatment is unsuccessful, surgical treatment is indicated. Surgical therapy should include resection of the hypertrophic spinous process, probably combined with revision of the nerve roots and division of adhesions. Between 1981 and 1993 six patients were treated surgically after long-lasting periods of conservative therapy. All patients were re-examined clinically and radiologically after a mean follow-up period of 2.9 years. In all but one patient a distinct release from lumbar back pain and/or sciatica was observed. Regarding this, the most important fact in de Anquin's disease is to be aware of this specific syndrome. If low-back pain can be traced to a hypertrophic spinous process the first choice of therapy should be conservative. In unsuccessful cases simple surgical resection probably combined with division of the adhesion can lead to significant release from pain and is recommended.

[Medium-term results in cement-free endoprosthetics: the Lord prosthesis]. / Mittelfristige Ergebnisse zementfreier Endoprothetik: Lord-Prothese.

In a clinical and radiological follow up 64 Lord-endoprostheses could be controlled after a meantime of 8.5 years. The positive judgement of the patients, which is caused by the reduction of pain, is in contrast to the poor improvement of gait and mobility. Radiological findings are suspicious for a higher rate of loosening of the cup and fractures of the shaft.

[Results of surgical therapy of bacterial sacroiliitis with primary arthrodesis]. / Ergebnisse der operativen Therapie der bakteriellen Sakroiliitis mit primärer Arthrodese.

Surgical treatment of pyogenic infections of the sacroiliac joint is indicated in cases of ineffective conservative treatment, abscess formation, septicemia, and neurological deficits. Between 1983 and 1990 in nine patients surgical treatment was performed for pyogenic sacroiliitis under this criteria. The surgical procedure included joint debridement, primary arthrodesis of the sacroiliac joint using a autologous bone graft, antibiotic therapy and postoperative immobilisation. Follow-up examination of 8 patients in average 47 months postoperatively revealed excellent functional and roentgenological results in 6 patients. Two patients suffered only from mild low-back pain, none of the eight patients demonstrated signs of a recurrent infection, one patient died due to complications of a long-lasting preoperative septicemia. Regarding these postoperative follow-up results surgical therapy including primary sacroiliac arthrodesis should be early considered, because this treatment has a low complication rate and the surgical technique is easy to perform and results are excellent or good in most of the patients.

Cephalic stimulation of gastrointestinal secretory and motor responses in humans.

The present study was designed (a) to investigate the cephalic phase of gastropancreatic secretion, antroduodenal motility, and regulatory peptide release in six healthy young men and (b) to assess its regulation by the cholinergic system and endogenous cholecystokinin. Sham feeding performed for 15 minutes induced a concurrent stimulation of gastropancreatic secretion, antroduodenal motility, and pancreatic polypeptide release that lasted for 30 minutes. Reappearance of interdigestive phases III was retarded in the post-sham-fed state. Atropine abolished secretory, motor, and pancreatic polypeptide responses to sham feeding and enhanced gastrin release. The cholecystokinin receptor antagonist loxiglumide did not attenuate pancreatic enzyme response but diminished antral motor response by 72% (P less than 0.05) and release of pancreatic polypeptide by 91% (P less than 0.05); it enhanced gastrin release and abolished retardation of reappearance of phase III with sham feeding. It is concluded that (a) there is a distinct cephalic phase of gastropancreatic secretion, antroduodenal motility, and pancreatic polypeptide release in humans that is primarily under cholinergic control and that (b) endogenous cholecystokinin is involved in antral motor, gastrin, and pancreatic polypeptide responses to sham feeding.