Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR.

BACKGROUND: Long-term survival of high-risk neuroblastoma patients is still below 50% despite intensive multimodal treatment. This trial aimed to address whether the addition of two topotecan-containing chemotherapy courses compared to standard induction therapy improves event-free survival (EFS) of these patients. PATIENTS AND METHODS: An open-label, multicenter, prospective randomized controlled trial was carried out at 58 hospitals in Germany and Switzerland. Patients aged 1-21 years with stage 4 neuroblastoma and patients aged 6 months to 21 years with MYCN-amplified tumors were eligible. The primary endpoint was EFS. Patients were randomly assigned to standard induction therapy with six chemotherapy courses or to experimental induction chemotherapy starting with two additional courses of topotecan, cyclophosphamide, and etoposide followed by standard induction chemotherapy (eight courses in total). After induction chemotherapy, all patients received high-dose chemotherapy with autologous hematopoietic stem cell rescue and isotretinoin for consolidation. Radiotherapy was applied to patients with active tumors at the end of induction chemotherapy. RESULTS: Of 536 patients enrolled in the trial, 422 were randomly assigned to the control arm (n = 211) and the experimental arm (n = 211); the median follow-up time was 3.32 years (interquartile range 1.65-5.92). At data lock, the 3-year EFS of experimental and control patients was 34% and 32% [95% confidence Interval (CI) 28% to 40% and 26% to 38%; P = 0.258], respectively. Similarly, the 3-year overall survival of the patients did not differ [54% and 48% (95% CI 46% to 62% and 40% to 56%), respectively; P = 0.558]. The response to induction chemotherapy was not different between the arms. The median number of non-fatal toxicities per patient was higher in the experimental group while the median number of toxicities per chemotherapy course was not different. CONCLUSION: While the burden for the patients was increased by prolonging the induction chemotherapy and the toxicity, the addition of two topotecan-containing chemotherapy courses did not improve the EFS of high-risk neuroblastoma patients and thus cannot be recommended. CLINICAL TRIALS. GOV NUMBER: NCT number 03042429.

Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia.

Some patients with acute myeloid leukemia (AML) who are in complete remission after induction chemotherapy harbor persisting pre-leukemic clones, carrying a subset of leukemia-associated somatic mutations. There is conflicting evidence on the prognostic relevance of these clones for AML relapse. Here, we characterized paired pre-treatment and remission samples from 126 AML patients for mutations in 68 leukemia-associated genes. Fifty patients (40%) retained ⩾1 mutation during remission at a variant allele frequency of ⩾2%. Mutation persistence was most frequent in DNMT3A (65% of patients with mutations at diagnosis), SRSF2 (64%), TET2 (55%), and ASXL1 (46%), and significantly associated with older age (P<0.0001) and, in multivariate analyses adjusting for age, genetic risk, and allogeneic transplantation, with inferior relapse-free survival (hazard ratio, 2.34; P=0039) and overall survival (hazard ratio, 2.14; P=036). Patients with persisting mutations had a higher cumulative incidence of relapse before, but not after allogeneic stem cell transplantation. Our work underlines the relevance of mutation persistence during first remission as a novel risk factor in AML. Persistence of pre-leukemic clones may contribute to the inferior outcome of elderly AML patients. Allogeneic transplantation abrogated the increased relapse risk associated with persisting pre-leukemic clones, suggesting that mutation persistence may guide postremission treatment.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.350.

Adaptive Designs with Discrete Test Statistics and Consideration of Overrunning.

BACKGROUND: Interim analyses are used in clinical trials in order to enable early decisions for medical, ethical, and economic reasons. However, it appears unfeasible to stop a trial during such an interim analysis. New patients will thus enter the trial while the interim analysis is ongoing. Moreover, depending on the event kinetics of the specific disease, the trial design, and the corresponding endpoints, some patients might still be unevaluable at the interim analysis due to not yet completed follow-up. Occurrence of these types of patients is characteristic for sequentially analyzed trials. Such patients are referred to as interim patients. In trials with multiple primary endpoints, another type of interim patients occurs. If some but not all null hypotheses can be rejected at the interim analysis, the trial might be continued to a second stage in order to answer the remaining questions. These second stage patients, however, provide new data to all trial questions including the already rejected ones and thus formally act as interim patients regarding the already rejected null hypotheses. Although all kinds of interim patients are not part of the interim analysis, the data collected on those patients have to be sent to the office of regulatory affairs and will be analyzed. If a smaller or contrasting treatment effect is observed in interim patients, this might lead to a withdrawal of an earlier superiority proof. OBJECTIVES: Presently, interim patients and their data are usually not considered in the confirmatory test. We offer a strategy to deal with interim patients in sequentially analyzed trials with discrete test statistics. The method covers sequentially analyzed single- and multi-arm trials with one or multiple primary endpoints. METHODS: When planning adaptive designs, it is common practice to assume that the stage-wise p-values are independent and standard uniformly distributed under the null hypothesis. In the context of discrete test statistics, this implies conservative tests. We provide an algorithm which iteratively optimizes an initially given design while adjusting for both discreteness of test statistics and interim patients. The algorithm is described verbally, graphically and formally to facilitate immediate implementation in computer software. RESULTS: The optimized design exploits the aspired significance level better and is more powerful than the initial one. The algorithm applies to fixed sample and planned flexible adaptive designs for single- and multi-arm trials with one or multiple primary endpoints. The benefit increases with the number of interim patients. CONCLUSIONS: When planning a trial with interim analyses, the rules for decisions must be adjusted to interim patients. Otherwise, the test procedure is conservative resulting in loss of power. This is essential in situations where the number of interim patients is important compared to the first stage, particularly in trials with multiple primary endpoints.

Development of curative therapies for Ewing sarcomas by interdisciplinary cooperative groups in Europe.

Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.

[Modern study designs and analysis methods in clinical research]. / Moderne Studiendesigns und Analysemethoden in der klinischen Forschung.

BACKGROUND: Progress in the field of medical research requires further development of clinical trial methodology to overcome the challenges resulting from small patient populations and restricted resources. METHODS: Classical single-stage designs with fixed sample sizes do not allow for interim analyses or design modifications. In contrast, adaptive designs adhere to established quality criteria while providing flexibility when conducting a clinical trial. In the face of new discoveries or information collected in the course of a trial, sample size adjustment, the selection of the target population and further design modifications can be performed. This enhances the chance of success of a clinical trial. Besides adaptive designs, classical approaches may be replaced or complemented by Bayesian methods. In a Bayesian approach prior knowledge can be efficiently included and hence the amount of information utilized in statistical analyses is increased. Furthermore, Bayes procedures allow the results of a statistical evaluation to be displayed very clearly. CONCLUSION: Modern approaches, such as adaptive designs and Bayesian designs overcome the challenges in clinical research due to enhanced flexibility and efficiency. In addition, both approaches can be combined.

No acute effects of an exposure to 50 ppm methyl methacrylate on the upper airways.

PURPOSE: The German MAK value of methyl methacrylate has been fixed at 50 ppm. The aim of this study was to evaluate possible acute effects of an exposure to 50 ppm methyl methacrylate on the upper airways of human subjects. METHODS: Twenty healthy subjects were exposed to 50 ppm methyl methacrylate and to air (sham) in an exposure chamber for 4 h according to a crossover design. Symptoms were assessed by the SPES questionnaire. Olfactory thresholds for n-butanol and mucociliary transport time were measured before and after exposure. Concentrations of interleukin 1ß and interleukin 8 were determined in nasal secretions taken after exposure. mRNA levels of interleukins 1ß, 6 and 8, tumor necrosis factor α, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein 1, and cyclooxygenases 1 and 2 were measured in nasal epithelial cells, obtained after exposure. Possible effects were investigated by semiparametric and parametric crossover analyses. RESULTS: The score of the item "irritation to the nose" was slightly elevated following exposure to methyl methacrylate (p ≤ 0.01). Olfactory functioning was not impaired. Mucociliary transport time did not change. Neither concentrations of interleukins in nasal secretions nor mRNA levels were elevated. CONCLUSION: Only minor irritating effects on the nose were observed. The acute exposure to 50 ppm methyl methacrylate did not cause any adverse effects. However, the results cannot be extrapolated to chronic exposure.

Treatment of recurrent primitive neuroectodermal tumors (PNET) in children and adolescents with high-dose chemotherapy (HDC) and stem cell support: results of the HITREZ 97 multicentre trial.

Early studies with high-dose chemotherapy for treatment of relapsed cerebral PNET had shown modest efficacy but considerable toxicity. The HIT97 national trial tested a nonrandomized but stratified relapse protocol using either intensive chemotherapy, potentially high dose, or oral chemotherapy. 72 patients (59 disseminated) whose primary treatment had been surgery (97 %), radiotherapy (88 %), and/or chemotherapy (95 %) were enrolled in the intensive chemotherapy arm at diagnosis of relapse or resistance. As a window for this study they received two courses of a 96-hour infusion with carboplatin and etoposide. A response (complete or partial remission) was documented by MRI. Responders received two more cycles of this therapy and stem cell collection, before they received HDC (carboplatin, etoposide, thiotepa) and stem cell support. All possibilities of local therapy were to be explored and applied. After two courses of chemotherapy there was a 52 % response rate (41/72 patients). The median PFS and OS for all 72 patients were 11.6 and 21.1 months. Patients with medulloblastoma had a longer PFS and OS (12.6 and 22.6 months) than those with other PNETs (3.1 and 12.3 months). Favourable prognostic features were no new signs of clinical impairment and localised disease at relapse diagnosis. For the 27 patients who received HDC the median PFS and OS were 8.4 and 20.2 months, respectively. HDC did not benefit patients with resistant cerebral PNET and was associated with profound haematological and mucosal toxicity (90-100 % grade III, IV), infections (50 % grade III and IV) and severe ototoxicity (50 % grade III, 12.5 % grade IV). Treatment related mortality was 8 %. There was low long-term survival and only 2/72 patients are in continuous remission. Adding HDC in patients who responded to the initial courses of chemotherapy did not improve survival. Patients with relapsed cerebral PNET who respond to conventional chemotherapy do not profit from further augmentation to HDC.

Acute effects of an exposure to 100 ppm 1-methoxypropanol-2 on the upper airways of human subjects.

The German MAK value of 1-methoxypropanol-2 has been fixed at 100 ppm. The aim of this study was to evaluate possible acute effects of an exposure to 100 ppm 1-methoxypropanol-2 on the upper airways of human subjects. Twenty subjects were exposed in a crossover design to 100 ppm 1-methoxypropanol-2 and to air in an exposure chamber for 4h. Subjective symptoms were assessed by questionnaire. Olfactory thresholds for n-butanol and mucociliary transport time were measured before and after exposure. Concentrations of interleukin 1ß and interleukin 8 were determined in nasal secretions taken after exposure. mRNA levels of interleukins 1ß, 6 and 8, tumor necrosis factor α, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein 1, and cyclooxygenases 1 and 2 were measured in nasal epithelial cells, obtained after exposure. Possible effects were investigated by semiparametric and parametric cross-over analyses. Subjects did not have any subjective irritating symptoms. The olfactory threshold was slightly elevated following exposure to 1-methoxypropanol-2. Mucociliary transport time did not change. Neither concentrations of interleukins in nasal secretions nor mRNA levels except for interleukin 1ß were higher after exposure to 1-methoxypropanol-2. In conclusion, the acute exposure to 100 ppm 1-methoxypropanol-2 did not cause clear-cut adverse effects in test subjects.

[Aventilatory mass flow during apnea : investigations on quantification]. / Aventilatorischer Massenfluss während Apnoe : Untersuchungen zur Quantifizierung.

BACKGROUND: Aventilatory mass flow (AVMF) is routinely used for apneic oxygenation in various clinical procedures but no data exist to quantitatively describe the gas flow. This study was designed to determine the amount of AVMF during the clinical situation of apnea to force spontaneous respiration at the end of anaesthesia with controlled ventilation. MATERIALS AND METHODS: A total of 200 patients undergoing anesthesia for routine surgery were examined. AVMF was analyzed with a high resolution, low gas stream, thermal mass flow analyzer. The intended recording time was 3 min. RESULTS: Measurement was reliably successful and suitable for evaluation in only 23 patients. AVMF-induced gas flow started on average 17.9 + or - 9.4 s after onset of apnea. Maximum flow was reached within 158 + or - 20 s and determined to be 135 + or - 32 ml/min. The slope of increase of gas flow showed a rapid oscillation corresponding to the heart rate in all patients and in 14 out of 23 patients a slow oscillation with a frequency of 8.9 + or - 1.8/min. CONCLUSIONS: During apnea AVMF develops in a non-linear fashion. The maximum flow observed is closely related to the estimated oxygen consumption. Heart rate synchronous flow variations are probably caused by intrathoracic volume variations due to heart action. The low frequency oscillations correspond to the frequency of Traube-Hering-Mayer waves.

[Tumor regression in malignant choroidal melanomas after transpupillary thermotherapy (TTT) versus ruthenium brachytherapy and sandwich therapy - a comparative analysis]. / Tumorregression maligner Aderhautmelanome nach Transpupillarer Thermotherapie (TTT) versus Ruthenium-Brachytherapie und Sandwichtherapie - eine vergleichende Analyse.

PURPOSE: The aim of this study was to evaluate tumour regression in a large series of choroidal melanomas, which were treated with three different eye-sparing treatment modalities. PATIENTS AND METHODS: Retrospective review of the treatment results in all eyes with malignant choroidal melanoma, which were treated in the University Eye Clinic of Mainz consecutively in the time span 1.1992 to 12.2000 with transpupillary thermotherapy (TTT, standard protocol Oosterhuis JA 1995), ruthenium brachytherapy (RB, tumor apex dose 150 Gy) or sandwich therapy (ST). One-step ST was defined as TTT followed by RB with 100 Gy tumor apex dose within 48 hours. The treatment of residual prominences with TTT secondary to RB after different time spans was called two-step ST. Follow-up was 2 years. RESULTS: 131 eyes with malignant choroidal melanoma (mean tumour thickness: 4.5 mm) were treated with RB (66 eyes), TTT (26 eyes) or ST (39 eyes). Preservation of the globe was achieved in 109 eyes (81 %). Local tumour control was found in small melanomas (prominence up to 3 mm) in 89 %, in large tumors (prominence 8 mm and higher) in 50 %. In a subgroup of small posterior melanomas (n = 70 eyes, prominence up to 4.5 mm, located posterior to the equator) local tumour control was noted in 91 %. The time span to reach local tumour control (Kaplan-Meier estimates) was the shortest after TTT (median: 20 weeks), compared with RB (48 weeks) and one-step ST (29 weeks). CONCLUSIONS: In choroidal melanomas the chance of local tumour control and preservation of the globe decreases with increase of the tumour prominence. In small choroidal melanomas with posterior location local tumour control was achieved significantly faster after TTT than after RB.

[Chiari II malformation. Supportive and predictive value of brainstem reflex and EAEP recordings]. / Chiari-II-Malformation. Supportiver und prädiktiver Wert der Hirnstammreflex- und FAEP-Diagnostik.

BACKGROUND: In about 20% of patients with Chiari II malformation brainstem signs and symptoms occur. Ventilatory dysfunction is the main cause of death in these patients. The indication for craniocervical decompression is based on clinical examination because supporting electrophysiological or radiological methods were lacking. METHODS: In a prospective study the clinical courses of 106 patients were documented during a 3-year period. In addition brainstem diagnostic procedures using the masseter reflex (MR), blink reflex (BR) and early auditory evoked potentials (EAEP) were done. Based on the model of binary logistic regression the odds ratio (OR) of progression over time was calculated. RESULTS: The combination of MR and late BR components showed the highest correlation with clinical findings (OR: 23). The highest predictive value regarding clinical progression over a 3-year period was shown by the combined evaluation of MR, late BR components and EAEP interpeak latency I-V (OR: 17.6). Signs and symptoms had no predictive value. CONCLUSIONS: Combined brainstem reflex recordings (MR and late BR components) support the clinical examination. To evaluate the long-term prognosis brainstem reflexes and EAEP recordings should be used.

An educational multimedia campaign improves stroke knowledge and risk perception in different stroke risk groups.

BACKGROUND AND PURPOSE: Stroke risk factor knowledge and individual risk perception are low in the general public. Our study aimed at identifying the educational effects of a multimedia campaign on stroke knowledge and risk perception in several subgroups at increased risk of stroke. METHODS: Telephone surveys were administered in a random sample of 500 members of the general public, before and immediately after an intense 3 months educational campaign using various mass and print media. RESULTS: A total of 32.7% of respondents considered themselves as being at risk of stroke before, and 41.9% (P < 0.01) after the intervention. Evaluation of stroke risk increased with number of appreciated individual stroke risk factors. Knowledge of different stroke risks varied considerably and proved to be especially high in obese individuals (98.7%) and smokers (97.9%) and particularly low in patients with coronary heart disease (80.6%). CONCLUSIONS: Our data indicate that educational programs and the introduction of stroke risk factors can increase stroke risk perception in the public. Even though some risk groups (smokers, obese) reveal a ceiling effect, future campaigns should focus on high risk populations remarkably underrating their risk, like those with coronary heart disease or the elderly.

No acute effects of an exposure to 50 ppm acetaldehyde on the upper airways.

OBJECTIVE: German MAK value of acetaldehyde has been fixed at 50 ppm to prevent from irritating effects. The threshold value is mainly based on animal experiments. The aim of this study was to evaluate acute effects of an exposure to 50 ppm acetaldehyde on the upper airways of human subjects. METHODS: Twenty subjects were exposed to 50 ppm acetaldehyde and to air in an exposure chamber for 4 h according to a crossover design. Subjective symptoms were assessed by questionnaire. Olfactory threshold for n-butanol and mucociliary transport time were measured before and after exposure. Concentrations of interleukin 1beta and interleukin 8 were determined in nasal secretions taken after exposure. mRNA levels of interleukins 1beta, 6 and 8, tumour necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein 1, and cyclooxygenases 1 and 2 were measured in nasal epithelial cells, gained after exposure. Possible effects were investigated by semiparametric and parametric crossover analyses. RESULTS: Exposure to acetaldehyde did not cause any subjective irritating symptoms. Olfactory threshold did not change. Mucociliary transport time increased insignificantly after exposure to acetaldehyde. Neither concentrations of interleukins in nasal secretions nor mRNA levels of inflammatory factors were higher after exposure to acetaldehyde. CONCLUSION: An acute exposure to 50 ppm acetaldehyde did not cause any adverse effects in test subjects.

Diabetes mellitus is a multivariate independent prognostic factor in endometrial carcinoma: a clinicopathologic study on 313 patients.

OBJECTIVE: The aim of this study was to analyse the influence of diabetes mellitus as a prognostic factor for overall survival in endometrial cancer. MATERIALS AND METHODS: Charts were reviewed from patients with endometrial carcinoma from 1985 to 2003. Data on clinicopathologic variables, adjuvant treatment, site of recurrence and survival were collected. The chi-square test was used to examine associations between variables. The Kaplan-Meier method was used for survival analysis and Cox's proportional hazards model for multiple regression analysis. RESULTS: Multivariate analysis revealed that diabetes mellitus, FIGO stage and depth of myometrial invasion were significantly associated with overall survival.

Infants with stage 4 neuroblastoma: the impact of the chimeric anti-GD2-antibody ch14.18 consolidation therapy.

BACKGROUND: Antibody treatment is considered tolerable and potentially effective in the therapy of neuroblastoma. We have analyzed the clinical data of infants < 1 year with stage 4 neuroblastoma with regard to the consolidation treatment. PATIENTS AND METHODS: Infants < 1 year with stage 4 neuroblastoma who completed initial treatment (6-8 chemotherapy cycles followed either by 4 cycles low dose oral chemotherapy or high dose chemotherapy with stem cell transplantation) without event were eligible for this trial. Consolidation therapy consisted of 6 cycles of antibody ch14.18 (20 mg/m(2) x d ch14.18 for 5 days every 2 months) or 12 months oral maintenance chemotherapy (MT). RESULTS: Of 59 evaluable patients, 31 received a total of 159 ch14.18 cycles, 16 received MT instead, and 12 had no further treatment. Fever (47 % of cycles), abnormal CRP without infection (25 %), rash (23 %), cough (16 %), and pain (8 %) were the main side effects. Univariate analysis found no difference in event free survival (3-year-EFS 80.5 +/- 7.1 %, 87.5 +/- 8.3 %, and 75.0 +/- 12.5 % for patients treated with antibody ch14.18, MT, and no further therapy, p = 0.433) and overall survival (3-year-OS 90.1 +/- 5.4 %, 93.8 +/- 6.0 %, and 91.7 +/- 8.0 % for patients treated with antibody ch14.18, MT, and no further therapy, p = 0.931). Multivariate analysis failed to demonstrate an advantage of antibody treatment. CONCLUSION: The outcome of infants with stage 4 neuroblastoma is good. Consolidation treatment with ch14.18 was tolerable but associated with fever, elevated CRP, rash, cough, and pain as side effects. Compared to oral maintenance chemotherapy and no consolidation treatment, ch14.18 treatment had no impact on the patients' outcome which confirms the results found in children > 1 year.

Functional capacity, obesity and hypothalamic involvement: cross-sectional study on 212 patients with childhood craniopharyngioma.

The aim of this study was to analyze the impact of hypothalamic involvement of craniopharyngioma on functional capacity (FC) and obesity in 212 patients with childhood craniopharyngioma. FC could be evaluated using an ability scale (Fertigkeitenskala Münster-Heidelberg [FMH]) in 174 patients with childhood craniopharyngioma. Obesity was quantified in 212 patients at the time of diagnosis and at the time of latest evaluation by body mass index SDS [BMI]. The influence of hypothalamic tumor involvement on FC and BMI was analyzed. Patients with hypothalamic involvement (n = 125) presented with higher BMI SDS at the time of diagnosis (p = 0.001) and at latest follow-up evaluation (p < 0.001). FC as measured by FMH percentiles was lower (p < 0.001) in patients with hypothalamic involvement when compared with patients without hypothalamic involvement. FC negatively correlated (p < 0.001) with BMI SDS (Spearman's Rho = -0.40) only in patients with hypothalamic involvement whereas no correlation between FC and BMI SDS was found in patients without hypothalamic involvement. We conclude that hypothalamic involvement of childhood craniopharyngioma had major impact on FC in survivors. Obesity resulted in impaired FC of patients with hypothalamic involvement. BMI at diagnosis was a sensitive parameter to identify patients at risk of severe obesity. Further analysis on this issue is performed in the prospective, multicenter surveillance study on children and adolescents with craniopharyngioma (KRANIOPHARYNGEOM 2000).

[Does a Combined Fascial Sling - Burch Colposuspension Display Advantages over a Fascial Sling alone for Treatment of Urinary Stress Incontinence in Females?]. / Bringt die Kombination einer Faszienzügelplastik mit der Kolposuspension nach Burch in der Therapie der weiblichen Stressinkontinenz Vorteile gegenüber der alleinigen Faszienzügelplastik?

PURPOSE: Despite the development of new surgical techniques, the fascial sling procedure remains an important surgical technique for the treatment of female urinary stress incontinence. An advantage of combining it with an additional Burch colposuspension has been suggested. The objective of our study was to evaluate retrospectively selected patients who had undergone a fascial sling procedure with and without Burch colposuspension. MATERIALS AND METHODS: Of a total of 390 females who underwent an incontinence operation at our department between 1990 and 1999, 56 patients had had a fascial sling plasty. A total of 50 patients (89 %) were followed for a median of 59.5 months. The median age was 60 years. 56 % of the patients displayed recurrent stress incontinence. The previous operations had been performed via a vaginal approach in 42.9 % and an abdominal approach in 57.1 %. The sling procedure used was that of Narik and Palmrich. Of the 50 patients, 14 had an additional Burch colposuspension. RESULTS: The continence rates (no pads) were for patients with a fascial sling procedure alone 63.9 % and for the combination of both operations 64.4 %. An improvement (1-3 pads) was seen in 27.8 % and 21.4 %, respectively. No changes were seen in 5.6 % and 7.1 % and impairment was seen in 2.7 % and 7.1 %, respectively. After a five-year follow-up, the total patient satisfaction rate was 78 %. CONCLUSIONS: The fascial sling is effective operative technique for treating female urinary stress incontinence, especially in severe and type III incontinence and in patients who had undergone previous operations for incontinence. The operation is safe and is the only technique that offers controlled overcorrection in desperate cases. An advantage of adding a Burch colposuspension to the fascial sling procedure was not detected in our patient group.

[Determination of the distribution volume of contrast media solutions injected intrahepatically: pre-pilot studies for intratumoral gene therapy]. / Bestimmung des Verteilungsvolumens von intrahepatisch injizierten Kontrastmittellösungen: Voruntersuchungen zur intratumoralen Gentherapie.

PURPOSE: Determination of the intrahepatic distribution volume of two contrast media (CM) by CT-guided application in an ex-vivo and an in-vivo model (pig liver). MATERIAL AND METHODS: In pig livers ex-vivo and in-vivo, 131 CT-guided injections of two different CM (Imagopaque(R), Visipaque(R)) were performed using catheters and cannula with and without side-holes and documented by spiral CT. The distribution pattern was assessed visually: interstitial, subcapsular, vascular/tubular, the distribution volume was quantified using a density mask (thresholds 70/400 HE). RESULTS: Purely interstitial applications were achieved more frequently in-vivo than ex-vivo (p = 0.001). There were no relevant differences between the two CM. Catheters without side-holes led to more interstitial CM depots than catheters with side-holes (p = 0.005). The mean distribution volume was larger with catheters with side-holes (ex-vivo 103 cm(3), in-vivo 19 cm(3)) than with catheters without side-holes (ex-vivo 67 cm(3), in-vivo 13 cm(3)) (p = 0,01). At the same time, the mean density with catheters with side-holes (102 HE) was lower than with catheters without side-holes (115 HE) (p = 0.005). CONCLUSION: Marked differences of the CM distribution volumes were observed between ex-vivo and in-vivo studies in the pig model. Catheters with side-holes are far superior to catheters without.

Comparison of peripheral bone and body axis skeleton in a rat model of mild-to-moderate renal failure in the presence of physiological serum levels of calcitropic hormones.

The skeleton is characterized by anatomic heterogeneity of metabolic turnover. Site-dependent differences in hormonal effects seem likely. Hyporesponsiveness of osteoclasts to parathyroid hormone (PTH) and probably calcitriol was recently demonstrated in the fifth lumbar vertebra of a rat model with moderate renal failure. We compared histomorphometric findings of the tibial head to these data. Histomorphometric measurements were carried out in sections of the right tibial head of pair-fed male Sprague-Dawley rats. Subtotally nephrectomized (SNx), parathyroidectomized (PTx), rats, which received either solvent or rat PTH(1-34) (100 ng/kg per hour) + calcitriol (5 pmol/kg per hour) via osmotic minipumps were compared with sham-operated controls. Results were compared with data from the fifth lumbar vertebra reported recently. Osteoclast numerical density and osteoclast surface density were lower in the tibial head and the lumbar vertebra of solvent-treated SNxPTx rats than in sham-operated controls (p < 0.05), and could not be returned to normal by the substitution of PTH + calcitriol (p < 0.05). On the other hand, there were differences between interventional effects on the tibial head and on the lumbar vertebra concerning parameters describing osteoblasts and trabecular bone volume. In the tibial head, osteoblast surface density was nearly unchanged in both interventions. Nevertheless, bone volume increased after SNxPTx without substitution of PTH + calcitriol (p < 0.05), and no further changes occurred after hormonal replacement. In contrast, osteoblast surface density in the lumbar vertebra was decreased slightly compared with values in sham-operated rats; a clear but nonsignificant increase occurred after the administration of calcitropic hormones. This was accompanied by unchanged trabecular bone volume after SNxPTx. Hormonal replacement, however, caused an increase in trabecular bone volume (p < 0.05), which represents an anabolic effect, which contrasts with findings from the tibial head. The different interventional effects on the lumbar spine and on peripheral bone, regarding the parameters reflecting the condition of osteoblasts, may be intrinsic to the uremic syndrome itself as well as to dissimilar growth manner, function, and mechanical requirements. The findings substantiate the site dependence of bone surface cell metabolism in renal failure and should be the subject of further study. Corresponding results with regard to bone resorption argue for a bone-site-independent, diminished response of osteoclasts to calcitropic hormones.