Referate

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Genetik

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Evidence for a hereditary neuroblastoma predisposition locus at chromosome 16p12-13

Hereditary predisposition to develop neuroblastoma (Online Mendelian Inheritance in Man 256700), a pediatric cancer of the sympathetic nervous system, segregates as an autosomal dominant Mendelian trait. We performed linkage analysis on seven families with two or more first-degree relatives affected with neuroblastoma to localize a hereditary neuroblastoma predisposition gene. A single interval at chromosome bands 16p12-13 was the only genomic region consistent with linkage (LOD(MAX) = 3.30 at D16S764). Identification of informative recombination events in linked families defined a 28.0-cM region between D16S748 and D16S769 that cosegregated with the disease in each pedigree. Loss of heterozygosity was identified in 5 of 11 familial neuroblastomas and 68 of 336 nonfamilial neuroblastomas (20.2%) at multiple 16p polymorphic loci. A 14.5-cM smallest region of overlap of somatic deletions was identified within the interval defined by linkage analysis (tel-D16S500-D16S412-cen). Taken together, these data suggest that a hereditary neuroblastoma predisposition gene (HNB1) is located at 16p12-13 and that disruption of this gene may contribute to the pathogenesis of nonfamilial neuroblastomas.     

Liposomal doxorubicin for treatment of metastatic chemorefractory vulvar adenocarcinoma

BACKGROUND: Primaryadenocarcinoma of the vulva is a rare entity, and for widely metastatic vulvar adenocarcinoma, no effective treatment has been established. CASE: A 65-year-old woman was diagnosed with regionally advanced vulvar adenocarcinoma, with bulky involvement of bilateral groin lymph nodes, and associated extramammary Paget's disease. Initial therapy consisted of multiagent chemotherapy and vulvar and groin irradiation, followed by radical vulvectomy with groin and pelvic lymph node dissection. She subsequently developed widely metastatic disease including brain, pulmonary, hepatic, osseus, and subcutaneous lesions. Treatment with liposomal doxorubicin (Doxil) resulted in dramatic regression of metastatic lesions and marked improvement in quality-of-life. She remains clinically well, greater than 1 year since initiating Doxil treatment for widely metastatic vulvar adenocarcinoma, and has surpassed 5 years of survival since her initial diagnosis. CONCLUSIONS: We report the first case of Doxil used for the treatment of metastatic chemorefractory vulvar adenocarcinoma. We observed that Doxil was a well-tolerated and effective agent for this gynecologic malignancy, and warrants further investigation.     

HER-2/neu overexpression and in vitro chemosensitivity to CMF and FEC in primary breast cancer

Available clinical and experimental data on the effect of HER-2/neu overexpression on chemosensitivity are controversial. It was the purpose of this in vitro study to define the association between HER-2/neu overexpression and the sensitivity to the chemotherapeutic drug combinations of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and 5-fluorouracil, epirubicin and cyclophosphamide (FEC) of breast cancer cells derived from 140 chemotherapy-naïve patients at the time of primary surgery. Both drug combinations were tested at six different concentrations ranging from 6.25–200% peak plasma concentration (PPC). Immunohistochemical detection of HER-2/neu overexpression was performed with the HER-2/neu antibodies, CB11, TAB250 and AO485, in the same tumor specimens. Immunoreactions were determined as negative (0/1+), weakly positive (2+) and strongly positive (3+). However, the antibodies varied in their degrees of sensitivity. Breast cancer samples with strong (3+) HER-2/neu overexpression demonstrated 90% growth inhibition (IC₉₀) at significantly lower PPC values, using the CB11 (p=0.048), TAB250 (p=0.007) and AO485 (p0.01) antibodies, and showed 50% growth inhibition (IC₅₀) at significantly lower PPC values, using the CB11 antibody (p=0.01) compared to their counterparts with lower levels of HER-2/neu expression. When analyzing the group of patients with intermediate and strong HER-2/neu overexpression (2+ and 3+), an association between HER-2/neu overexpression and increased chemosensitivity was seen with the TAB250 (p=0.044) and AO485 (p=0.032) antibodies, but not with the CB11 antibody (p=0.8) at the IC₉₀ level. Differences in chemosensitivity between samples with strong HER-2/neu overexpression and those with lower levels were then analyzed separately for CMF and FEC. Both regimens achieved 90% tumor growth inhibition at lower PPC values in samples with strong HER-2/neu overexpression (3+) compared to their counterparts with lower expression levels (AO485 p=0.011 for CMF, and p=0.09 for FEC). Cumulative concentration-response plots of tumors responding in vitro with 90% tumor cell inhibition showed a stronger dose dependence for both CMF and FEC among tumor samples with strong HER-2/neu overexpression compared to those with lower levels of expression. In conclusion, the data show that HER-2/neu overexpression was not associated with in vitro drug resistance to CMF or FEC. In contrast, tumors with strong HER-2/neu overexpression demonstrated increased dose-dependent in vitro sensitivity to both the FEC and CMF regimens.     

Roll-over shapes of the able-bodied knee-ankle-foot system during gait initiation, steady-state walking, and gait termination

A few investigators have described the movement of the center of pressure (COP) of the ground reaction force and the activation patterns of the lower limb muscles during gait initiation and termination. This study examines the effective rocker (roll-over shape) behavior of the knee-ankle-foot (KAF) system during gait initiation, steady-state walking (i.e. constant speed gait), and gait termination. The KAF roll-over shapes were characterized by transforming COP data of 10 able-bodied subjects from a laboratory-based coordinate system into a leg-based coordinate system. The resulting roll-over shapes (effective rockers) were characterized using a circular arc model. The KAF roll-over shapes exhibit an overall "flexed" orientation during the first step of gait initiation and an "extended" orientation during the last step of gait termination. Understanding the behavior of the anatomical KAF system during gait initiation and termination may aid in the design of prosthetic components, i.e. mechanical devices that replace complete anatomical structures. Prostheses that intend to mimic the overall behavior of physiological KAF systems (biomimetic designs) could be manufactured using approaches that are much simpler than attempting to reconstruct the complexity of the lower limb.     

Fibre supplementation for the prevention of type 2 diabetes and improvement of glucose metabolism: the randomised controlled Optimal Fibre Trial (OptiFiT)

Aims/hypothesis

Insoluble cereal fibres have been shown in large prospective cohort studies to be highly effective in preventing type 2 diabetes, but there is a lack of interventional data. Our 2 year randomised double-blind prospective intervention study compared the effect of an insoluble oat fibre extract with that of placebo on glucose metabolism and incidence of diabetes.

Methods

A total of 180 participants with impaired glucose tolerance underwent a modified version of the 1 year lifestyle training programme PREvention of DIAbetes Self-management (PREDIAS) and were randomised to receive a fibre supplement (n?=?89; 7.5 g of insoluble fibre per serving) or placebo (n?=?91; 0.8 g of insoluble fibre per serving) twice daily for 2 years. Eligible participants were men and women, were at least 18 years old and did not report corticosteroid or other intensive anti-inflammatory treatment, fibre intolerance or any of the following disorders: overt diabetes, chronic or malignant disease, or severe cardiopulmonary, endocrine, psychiatric, gastrointestinal, autoimmune or eating disorder. Participants were recruited at two clinical wards in Berlin and Nuthetal. The allocation was blinded to participants and study caregivers (physicians, dietitians, study nurses). Randomisation was conducted by non-clinical staff, providing neutrally numbered supplement tins. Both supplements were similar in their visual, olfactory and gustatory appearance. Intention-to-treat analysis was applied to all individuals.

Results

After 1 year, 2 h OGTT levels decreased significantly in both groups but without a significant difference between the groups (fibre ?0.78?±?1.88 mmol/l [p?≤ 0.001] vs placebo ?0.46?±?1.80 mmol/l [p?=?0.020]; total difference 0.32?±?0.29 mmol/l; not significant). The 2 year incidence of diabetes was 9/89 (fibre group) compared with 16/91 (placebo group; difference not significant). As secondary outcomes, the change in HbA_1c level was significantly different between the two groups (?0.2?±?4.6 mmol/mol [?0.0?±?0.0%; not significant] vs +1.2?±?5.2 mmol/mol [+0.1?±?0.0%; not significant]; total difference 1.4?±?0.7 mmol/mol [0.1?+?0.0%]); p?=?0.018); insulin sensitivity and hepatic insulin clearance increased in both groups. After 2 years, improved insulin sensitivity was still present in both groups, although the effect size had diminished. Separate analysis of the sexes revealed a significantly greater reduction in 2 h glucose levels for women in the fibre group (?0.88?±?1.59 mmol/l [p?≤ 0.001] vs ?0.22?±?1.52 mmol/l [p?=?0.311]; total difference 0.67?±?0.31 mmol/l; p?=?0.015). Levels of fasting glucose, adipokines and inflammatory markers remained unchanged in the two groups. Significantly increased fibre intake was restricted to the fibre group, despite dietary counselling for both groups. No severe side effects occurred.

Conclusions/interpretation

We cannot currently provide strong evidence for a beneficial effect of insoluble cereal fibre on glycaemic metabolism, although further studies may support minor effects of fibre supplementation in reducing glucose levels, insulin resistance and the incidence of type 2 diabetes.Trial registration: clinicaltrials.gov NCT01681173Funding: German Diabetes Foundation (grant no. 232/11/08)

     

Cost of outpatient care in patients with inflammatory bowel disease in a German University Hospital

BACKGROUND AND AIM: Because of its long duration, inflammatory bowel disease (IBD) causes high use of health services and high lifetime costs for medical care. The aim of the present study was to measure the costs of outpatient care in patients with IBD in a German University Hospital and to identify potentially relevant determinants of costs. METHODS: The use of resources of 599 outpatient patients treated at a German University Hospital (65% Crohn's disease [CD] and 26% ulcerative colitis [UC]) was measured using a routine database. Costs of medical services (diagnostics and treatment) were considered as well as costs of medication. Resource use was valued using fee schedules for hospital services and pharmacy prices for drugs. RESULTS: The mean cost of one outpatient visit was Euros 162, including physician costs, laboratory costs, and costs of diagnostic procedures following the visit. For a subgroup of 272 patients, the mean annual cost for outpatient care was Euros 3171. Medication accounted for 85% of the total annual costs. Potential determinants, such as main diagnosis (CD or UC), sex, age, localization of disease, and occurrence of anemia, had no influence on costs, whereas complications of IBD and use of corticosteroids showed an impact on annual costs. CONCLUSIONS: This is the first time that the structure and range of outpatient treatment costs for IBD have been demonstrated for a German hospital.