Obesity as an independent risk factor for decreased survival in node-positive high-risk breast cancer.

Obese breast cancer patients have a higher risk of lymph node metastasis and a poorer prognosis compared to patients with normal weight. For obese women with node-positive breast cancer, an association between body weight and prognosis remains unclear. In this retrospective study, we analyzed patient data from the Phase-III ADEBAR trial, in which high-risk breast cancer patients (pT1-4, pN2-3, pM0) were randomized into a docetaxel-based versus epirubicin-based chemotherapy regimen. Patients were grouped according to their BMI value as underweight/normal weight (BMI < 25 kg/m(2); n = 543), overweight (BMI 25-29.9 kg/m(2); n = 482) or obese (BMI ≥ 30 kg/m(2); n = 285). Overweight and obese patients were older, had larger tumors and were more likely to be postmenopausal at the time of diagnosis compared to underweight/normal-weight patients (all p < 0.001). Multivariate Cox regression analyses adjusting for age and histopathological tumor features showed that obese patients had a significantly shorter disease-free survival (DFS; HR 1.43; 95 % CI 1.11-1.86; p = 0.006) and overall survival (OS; HR 1.56; 95 % CI 1.14-2.14; p = 0.006) than non-obese patients. Subgroup analyses revealed that the differences in DFS and OS were significant for postmenopausal but not for premenopausal patients, and that the survival benefit of non-obese patients was more pronounced in women with hormone-receptor-positive disease. Obesity constitutes an independent, adverse prognostic factor in high-risk node-positive breast cancer patients, in particular for postmenopausal women and women with hormone-receptor-positive disease.

Efficacy and safety of pharmacological treatments for acute Lyme neuroborreliosis - a systematic review.

BACKGROUND AND PURPOSE: Our aim was to evaluate the available evidence for pharmacological treatment of acute Lyme neuroborreliosis as a basis for evidence-based clinical recommendations in a systematic review. METHODS: A systematic literature search of Medline, EMBASE, the Cochrane Library and three trial registries was performed. Randomized controlled trials (RCTs) and non-randomized studies (NRS) were evaluated. Risk of bias was assessed using the Cochrane risk of bias tools. The primary outcome was 'residual neurological symptoms' whilst the secondary outcomes were disability, quality of life, pain, fatigue, depression, cognition, sleep, adverse events and cerebrospinal fluid pleocytosis. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: After screening 5779 records, eight RCTs and eight NRS were included. Risk of bias was generally high. No statistically significant difference was found between doxycycline and beta-lactam antibiotics in a meta-analysis regarding residual neurological symptoms at 4-12 months [risk ratio (RR) 1.27, 95% confidence interval (CI) 0.98-1.63, P = 0.07] or adverse events (RR 0.82, 95% CI 0.54-1.25, P = 0.35). Significantly fewer neurological symptoms for cefotaxime compared with penicillin were found (RR 1.81, 95% CI 1.10-2.97, P = 0.02). Adverse events were significantly fewer for penicillin (RR 0.56, 95% CI 0.38-0.84, P = 0.005). CONCLUSIONS: Evidence regarding pharmacological treatment of acute Lyme neuroborreliosis is scarce and therefore insufficient to recommend preference of beta-lactam antibiotics over doxycycline or vice versa. However, due to considerable imprecision, relevant differences between treatments cannot be excluded. No evidence suggesting benefits of extended antibiotic treatments could be identified. Further well-designed trials are needed. Individual treatment decisions should address patients' preferences and individual conditions like prior allergic reactions.

Methodological quality of guidelines for management of Lyme neuroborreliosis.

BACKGROUND: Many aspects of clinical management of Lyme neuroborreliosis are subject to intense debates. Guidelines show considerable variability in their recommendations, leading to divergent treatment regimes. The most pronounced differences in recommendations exist between guidelines from scientific societies and from patient advocacy groups. Assessment of the methodological quality of these contradictory guideline recommendations can be helpful for healthcare professionals. METHODS: Systematic searches were conducted in MEDLINE and databases of four international and national guideline organizations for guidelines on Lyme neuroborreliosis published from 1999-2014. Characteristics (e.g., year of publication, sponsoring organization) and key recommendations were extracted from each guideline. Two independent reviewers assessed the methodological quality of each guideline according to the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. AGREE II scores from guidelines developed by scientific societies and from patient advocacy groups were compared across domains. RESULTS: We identified eight eligible guidelines of which n = 6 were developed by scientific societies and n = 2 by patient advocacy groups. Agreement on AGREE II scores was good (Cohen's weighted kappa = 0.87, 95% CI 0.83-0.92). Three guidelines, all from scientific societies, had an overall quality score of ≥ 50%. Two of them were recommended for use according to the AGREE II criteria. Across all guidelines, the AGREE II domain with the highest scores was "Clarity of Presentation" (65, SD 19%); all other domains had scores < 50% with the domain "Applicability" having the lowest scores (4, SD 4%). Guidelines developed by scientific societies had statistically significantly higher scores regarding clarity of presentation than guidelines from patient advocacy groups (p = 0.0151). No statistically significant differences were found in other domains. CONCLUSIONS: Current guidelines on Lyme neuroborreliosis vary in methodological quality and content. Health care providers and patients need to be aware of this variability in quality when choosing recommendations for their treatment decisions regarding Lyme neuroborreliosis. No statement can be given on quality of content and validity of recommendations, as these issues are not subject to assessment with the AGREE II tool and are prone to individual interpretation of the available evidence by the corresponding guideline panels. To enhance guideline quality, guideline panels should put more emphasis on linking recommendations to the available evidence, transparency in reporting how evidence was searched for and evaluated, and the implementation of recommendations into clinical practice.

[Studies and Publication Practice in Pediatric Hematology and Oncology in Germany--An Analysis of the Period 1970-2006]. / Studien und Publikationspraxis in der PädiatrischenHämatologie und Onkologie in Deutschland--Analyseder Jahre 1970­2006.

BACKGROUND: Several therapy optimization studies (TOSs) for the treatment of hematologic and oncologic disorders in children and adolescents have been conducted in Germany. The publication of research results is necessary to ensure that future studies are well designed and based on relevant and unanswered questions. This retrospective cohort study was conducted to analyze the study- and publication practice in this field. METHODS: All study protocols in the field of the pediatric oncology and hematology in Germany were collected. Relevant data from study protocols were extracted, beginning with 1) general information about the study protocol, and 2) information about each methodological trial. In a second step, the publication practice was characterized by searching in electronic databases and by contacting principal investigators. Relevant Data of each publication was extracted. RESULTS: The research activity has increased significantly in the past few years. The found publication rate of 85% represents an outstanding publication practice. Additionally, German, as being the main publication language a few decades ago, has been almost completely replaced with English. An acceptable methodological conduct was observed in the analyzed study protocols. DISCUSSION AND CONCLUSION: Studies have been principally based on the concept of TOS, without considering a detailed breakdown into each methodological trial. A markedly subdivision of studies into methodologically identifiable trials would allow a clear definition of their parameters, while increasing transparency of the study conduct and its results.

Survival of Salmonella on cuts of beef carcasses subjected to dry aging.

AIMS: The aim of this study was to determine the survival of 15 different strains of Salmonella of selected serotypes during prolonged cold storage of beef. METHODS AND RESULTS: Fifteen strains of eight different serotypes of Salmonella were spiked onto fresh cuts beef portions, and the survival was followed during storage in a laboratory cooling system. Over a 14-day period, all strains were reduced significantly in numbers; however, strains of Salmonella Typhimurium DT104 and Salmonella Enteritidis PT4 and PT8 survived significantly longer than strains of the serovars Dublin, Derby, Infantis and Newport. For five selected strains, the observations were verified in a pilot plant cooling facility mimicking industrial cooling. No significant differences in reduction were found between the two cooling methods. CONCLUSIONS: A significant reduction in Salmonella can be obtained by dry aging of beef during cold storage but the survival is strain dependent. SIGNIFICANCE AND IMPACT OF THE STUDY: From a hygienic point of view, cold storage of unpacked beef, which is still performed in small slaughterhouses, is a good alternative to vacuum packaging.

Epirubicin and cyclophosphamide versus epirubicin and docetaxel as first-line therapy for women with metastatic breast cancer: final results of a randomised phase III trial.

BACKGROUND: This randomised phase III trial was carried out to compare the efficacy and safety of epirubicin and cyclophosphamide (EC) with epirubicin and docetaxel (Taxotere) (ED) as first-line chemotherapy for metastatic breast cancer. PATIENTS AND METHODS: Patients (n = 240) were randomly assigned to receive either ED (epirubicin 75 mg/m(2) and docetaxel 75 mg/m(2)) or EC (epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2)). The primary end point was objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: ORR for patients randomly assigned to receive EC and ED were 42% and 47%, respectively (P = 0.63). Median PFS [10.1 versus 10.3 months; hazard ratio (HR) 0.98; log-rank P = 0.38] and OS (19.9 versus 30.0 months; HR 0.663; log-rank P = 0.21) were comparable in both arms. Although grade 3/4 leucopenia occurred more frequently with ED (81% versus 73%; P = 0.01), there were no significant differences in the incidence of febrile neutropenia and grade 3/4 infections. Grade 3/4 non-haematologic toxicity was infrequent in both arms. Congestive heart failure was observed in one patient in each arm. CONCLUSION: In this randomised trial, no differences in the efficacy study end points were observed between the two treatment arms.

Sequential chemotherapy with carboplatin followed by weekly paclitaxel in advanced ovarian cancer: results of a multicenter phase II study of the northeastern German society of gynecological oncology.

BACKGROUND: For the adjuvant setting of advanced ovarian cancer (AOC) after primary radical surgery the combination of paclitaxel and platinum in a 3-week schedule has emerged as the current standard. In preclinical studies additional anti-angiogenic effects of low dose paclitaxel infusion were demonstrated. A sequential schedule of carboplatin and paclitaxel has the potential to improve the therapeutic index. METHODS: In this multicenter phase II trial four cycles of carboplatin at a dose of AUC 5 (d1/q21d) followed by 12 cycles of weekly paclitaxel at a dose of 80 mg/m(2) (d1/q7d) were applied after primary radical surgery. Eligible were all optimally or sub-optimally debulked patients with FIGO IA-IV ovarian cancer. All patients with hemoglobin levels <12 mg/dl received erythropoietin additionally. RESULTS: Between July 2003 and May 2005, 105 patients from 27 institutions were enrolled. The median age was 60 years (range: 23-80 years). A median number of 16 courses (range 1-16) were applied. The incidence of non-hematological toxicities was very low. Only 41% of patients experienced alopecia (grade 1-2). Neurotoxicity (grade 3-4) was not observed. Grade 3-4 hematological toxicity (43% of all patients) included thrombocytopenia (17%), anemia (3%), leucopenia (23%), and neutropenic fever (0%). Ninety-seven percent received erythropoietin. Thromboembolic events (4%) were not increased in patients who received erythropoietin. After a median time of 23 months (range: 1-42 months) 32 patients had died, and the median overall survival was not reached. The progression-free survival was 25.4 months (95% CI: 18.8-40+). CONCLUSION: These results suggest that this sequential regimen using weekly paclitaxel represents an efficacious and well-tolerated regimen. A randomized study comparing this new schedule with the conventional 3-week protocol is warranted.

Genetic Control of Flower Development by Homeotic Genes in Antirrhinum majus.

Homeotic mutants have been useful for the study of animal development. Such mutants are also known in plants. The isolation and molecular analysis of several homeotic genes in Antirrhinum majus provide insights into the underlying molecular regulatory mechanisms of flower development. A model is presented of how the characteristic sequential pattern of developing organs, comprising the flower, is established in the process of morphogenesis.

Genetic engineering of parthenocarpic plants.

Transgenic tobacco and eggplants expressing the coding region of the iaaM gene from Pseudomonas syringae pv. savastanoi, under the control of the regulatory sequences of the ovule-specific DefH9 gene from Antirrhinum majus, showed parthenocarpic fruit development. Expression of the DefH9-iaaM chimeric transgene occurs during flower development in both tobacco and eggplant. Seedless fruits were produced by emasculated flowers. When pollinated, the parthenocarpic plants produced fruits containing seeds. In eggplant, the genetic manipulation allowed fruit set and growth under environmental conditions prohibitive for fruit setting in the untransformed line, which did not set fruit at all. Under normal environmental conditions, production of marketable fruits took place from pollinated and unpollinated transgenic flowers, while flowers of untransformed control plants did produce fruits of marketable size only from fertilized flowers.

Monte Carlo simulation of ruthenium eye plaques with GEANT4: influence of multiple scattering algorithms, the spectrum and the geometry on depth dose profiles.

Previous studies show remarkable differences in the simulation of electron depth dose profiles of ruthenium eye plaques. We examined the influence of the scoring and simulation geometry, the source spectrum and the multiple scattering algorithm on the depth dose profile using GEANT4. The simulated absolute dose deposition agrees with absolute dose data from the manufacturer within the measurement uncertainty. Variations in the simulation geometry as well as the source spectrum have only a small influence on the depth dose profiles. However, the multiple scattering algorithms have the largest influence on the depth dose profiles. They deposit up to 20% less dose compared to the single scattering implementation. We recommend researchers who are interested in simulating low- to medium-energy electrons to examine their simulation under the influence of different multiple scattering settings. Since the simulation and scoring geometry as well as the exact physics settings are best described by the source code of the application, we made the code publicly available.

A cross-sectional field study on potential associations between feed quality measures and usage of antimicrobials in commercial mink (Neovison vison).

Feed quality is generally assumed to affect health status in animal production. In previous studies, the feed producer has been found to affect the occurrence of gastrointestinal disease and antimicrobial use in Mink (Neovison vison). Mink are fed with moist, freshly produced feed, based on perishable ingredients. The objective of this study was to investigate the potential effect of specific feed parameters on antimicrobial use on herd level. The study was cross-sectional, including 1472 mink herds, responsible for 97% of oral antimicrobials prescribed for Danish mink during the study period, 2012-2014. Data were obtained from the national veterinary prescription database (VetStat), Kopenhagen Fur database, and the Voluntary Feed Control (Mink producers Organization). All feed batches subject to feed control were included. A multi-variable variance analysis was carried out analysing the effect of the feed parameters total volatile nitrogen, dry matter, crude protein and fat; total bacterial count (21°C), and counts of sulphite producing bacteria (21°C), Clostridium spp., faecal cocci (FC) (44°C), yeast, and mould; presence of Salmonella spp. and Clostridium perfringens (dichotome). Three outcome variables were applied: prescription of oral antimicrobial on herd level within time slots of 3, 5 or 7days after feeding of an included batch. Two binomial models were developed, adjusting for significant effects (p<0.0001) of Ps. aeruginosa infection, herd size, month (season) and year. Antimicrobial prescription was significantly (p<0.0001) associated with FC (all time slots, both models). A negative association (p<0.0001) with crude protein on antimicrobial prescription within a 7day slot suggested an association between low content of crude protein and antimicrobial use. The associations need to be confirmed in controlled studies, and ideally, potential causalities should be investigated. The perspective of such findings could be the development of tests for control of feed ingredients prior to use in the feed production.

Study participation improves treatment strategies and individual patient care in participating centers.

BACKGROUND: The ADEBAR study is a prospective multicenter Phase III trial to examine whether high-risk breast cancer patients > or =4 involved axillary lymph nodes) benefit from a sequential anthracycline-docetaxel regimen compared to standard chemotherapy with anthracyclines. With a median recruitment of 33 patients per month at 198 actively-recruiting centers, the ADEBAR study was the best recruiting study in Germany until the end of the trial. MATERIALS AND METHODS: A standardized questionnaire was sent to all participating centers in order to determine the extent to which treatment strategies and patient care are affected by participation in the ADEBAR study. The questionnaire covered 5 areas of interest: previous inclusion of patients at the same tumor stage in other studies, the type of chemotherapy received by comparable patients previously outside the study, change in the intensity of medical care since participating in the ADEBAR study, the information gained through participation in the study and changes in the overall quality of medical care. RESULTS: 51.0% (n=98) of the questionnaires were returned, from which 3 were excluded from the analysis due to being incomplete. In the year preceding the ADEBAR study, 63.2% of participating centers had not entered their high-risk patients into a clinical trial. Before participating in the ADEBAR protocol, 44.2% of patients with the same indication had received inadequate therapy by today's standards, such as CMF, EC/CMF or 4x EC. 59.0% of the centers noted an increase in the intensity of patient care as a result of participation in the study, independent of the care provided purely because of the study. By being part of a research network, with a regular flow of information via newsletters, study meetings and the like, 80.0% noted an improvement in their professional knowledge in the field of breast cancer. Moreover, 31.6% of the centers reported an improvement in the overall quality of their patient care since the start of the trial. CONCLUSION: The results of the survey demonstrate that both physicians and patients benefit from participation in clinical trials as this is associated with optimized decision-making as regards therapy and patient care.

Prevalence and spectrum of residual symptoms in Lyme neuroborreliosis after pharmacological treatment: a systematic review.

Controversy exists about residual symptoms after pharmacological treatment of Lyme neuroborreliosis. Reports of disabling long-term sequels lead to concerns in patients and health care providers. We systematically reviewed the available evidence from studies reporting treatment of Lyme neuroborreliosis to assess the prevalence and spectrum of residual symptoms after treatment. A literature search was performed in three databases and three clinical trial registers to find eligible studies reporting on residual symptoms in patients after pharmacological treatment of LNB. Diagnosis must have been performed according to consensus-derived case definitions. No restrictions regarding study design or language were set. Symptom prevalence was pooled using a random-effects model. Forty-four eligible clinical trials and studies were found: 8 RCTs, 17 cohort studies, 2 case-control studies, and 17 case series. The follow-up period in the eligible studies ranged from 7 days to 20 years. The weighted mean proportion of residual symptoms was 28 % (95 % CI 23-34 %, n = 34 studies) for the latest reported time point. Prevalence of residual symptoms was statistically significantly higher in studies using the "possible" case definition (p = 0.0048). Cranial neuropathy, pain, paresis, cognitive disturbances, headache, and fatigue were statistically significantly lower in studies using the "probable/definite" case definition. LNB patients may experience residual symptoms after treatment with a prevalence of approximately 28 %. The prevalence and spectrum of residual symptoms differ according to the applied case definition. Symptoms like fatigue are not reported in studies using the "probable/definite" case definition. As the "possible" case definition is more unspecific, patients with other conditions may be included. Reports of debilitating fatigue and cognitive impairment after LNB, a "post-Lyme syndrome", could therefore be an artifact of unspecific case definitions in single studies.

Factors associated with usage of antimicrobials in commercial mink (Neovison vison) production in Denmark.

The American mink (Neovison vison) is used for commercial fur production in Denmark. In recent years, antimicrobial prescription for Danish mink has been increasing. In this study, the patterns and trends in antimicrobial use in mink were described and a multi-variable variance analysis was carried out with the objective of identifying risk factors for antimicrobial use on herd level. The study was based on register data for 2007-2012. Information on antimicrobial use was obtained from the national database VetStat, monitoring all medicinal products used for animals on prescription level. Data on microbiological feed quality was obtained from the Voluntary Feed Control under the Mink producers Organization, and data on herd size and the relation between farm and feed producer was obtained from the registers at Kopenhagen Fur, based on yearly reporting from the mink producers. Descriptive analysis showed a clear significant effect of season on antimicrobial use, with a peak in "treatment proportions", TP (defined daily doses per kg biomass-days) in May, around the time of whelping, and a high level in the following months. In autumn, a minor peak in antimicrobial use occurred throughout the study period. From 2007 to 2011, a 102% increase in annual antimicrobial TP was noted; on herd level, the increase was associated with an increasing frequency of prescription, and a decrease in the amounts prescribed in months with prescription. A binomial model showed that on herd level, the annual number of months with antimicrobial prescription was significantly (p<0.01) affected by feed producer, veterinarian, disease (specific laboratory diagnosis) infection, herd size and year, with an interaction between feed producer and year. A log-normal model showed that in months with antimicrobial use, the TP on herd level was significantly (p<0.001) affected by year, month (season), feed producer, feed quality score, veterinarian, herd size and laboratory confirmed diagnosis of specific infections; additionally the interaction terms year×feed producer and herd size×month were significant (p<0.001). In conclusion, antimicrobial use on herd level was significantly associated with the microbiological food quality, the feed producer, and the veterinarian. The prescription patterns varied significantly between veterinarians, and some veterinarians were associated with both larger and more frequent prescriptions of antimicrobials at herd level. Herd size is associated with different prescription patterns. Finally, infection with Pseudomonas aeruginosa, astrovirus, influenza virus and Salmonella spp. was associated with an increase in antimicrobial use.

Development of an Open-Source Tractor Driving Simulator for Tractor Stability Tests.

Developing devices for stability monitoring and rollover alerts is a promising possibility to prevent overturn events, which pose a severe risk to tractor operators. However, performing relevant tests with operators in the field is dangerous and impractical. As an alternative, this work identifies the challenges of simulating a tractor driving environment in a laboratory and details the solutions put in place to develop a tractor driving simulator at Penn State University. The simulator includes an instrumented tractor cab mounted on a custom motion base, a 2.43 m tall, 360° high-definition screen, a sound system, and a nine-computer network running open-source software that can be used to conduct experiments and simulate driving scenarios relevant to tractor instabilities. The system is used for an experiment that evaluates the driver's ability to perceive tilt angles at various tilt and roll combinations. Pilot-test results show that roll and pitch are systematically overestimated, producing perceptual errors that are unbiased, independent for roll and pitch, and typically have magnitudes of 4°. These results can aid the development of instability monitoring systems by considering human tilt perception to set alert thresholds. Future projects and applications of the tractor driving simulator are also discussed.

Farm specific risk factors for Campylobacter colonisation in Danish and Norwegian broilers.

Campylobacteriosis has become the leading bacterial zoonosis in humans in the European Union and other developed countries. There are many sources of human Campylobacter infections, but broilers and broiler meat have been shown to be the most important. In order to implement effective interventions that reduce the probability of Campylobacter colonisation of broiler flocks, it is essential to fully understand the risk factors involved. We present a bi-national risk factor survey comprising Campylobacter data from more than 5200 Danish and Norwegian indoor, conventional broiler flocks and the responses to a standardised questionnaire, with more than 40 explanatory variables from 277 Danish and Norwegian farms. We explored several models by using different combinations of the Danish and Norwegian data, including models with single-country datasets. All models were analysed using a generalized linear model using backwards elimination and forward selection. The results show that Norwegian broiler flocks had a lower risk of being colonised than Danish flocks. Farm specific variables that increased the risk of flocks becoming colonised with Campylobacter in both countries were: broiler houses older than five years; longer downtime (no. of days between flocks), probably a consequence of longer downtimes being associated with less focus on maintaining a high biosecurity level; broiler houses without a separate ante-room or barrier; and the use of the drinker nipples with cups or bells compared with nipples without cups. Additional country specific risk factors were also identified. For Norway, the risk of colonisation increased with increasing numbers of houses on a farm and when the water used for the broilers originated from surface water or bore holes instead of mains. For Denmark, having boot dips or low stocking density increased the risk of a flock becoming Campylobacter positive. The different model approaches allowed us to explore the effect of having a large number of data available to identify the significant variables. To a large extent, the country specific models identified risk factors that were also found in the bi-national model. However, the bi-national model identified more risk factors than the country specific models. This indicated that combining the data sets from the two countries did not disrupt the results but was beneficial due to the greater strength achieved in the statistical analyses and the possibility of examining interactions terms with the variable Country.

Toxicity Assessment of a Phase III Study Evaluating FEC-Doc and FEC-Doc Combined with Gemcitabine as an Adjuvant Treatment for High-Risk Early Breast Cancer: the SUCCESS-A Trial.

Introduction: This paper aims to evaluate the toxicity profile of additive gemcitabine to adjuvant taxane-based chemotherapy in breast cancer patients. Methods: Patients enrolled in this open-label randomized controlled Phase III study were treated with 3 cycles of epirubicin-fluorouracil-cyclophosphamide (FEC) chemotherapy followed by 3 cycles of docetaxel with those receiving 3 cycles of FEC followed by 3 cycles of gemcitabine-docetaxel (FEC-DG). 3690 patients were evaluated according to National Cancer Institute (NCI) toxicity criteria (CTCAE). The study medications were assessed by the occurrence of grade 3-4 adverse events, dose reductions, postponements of treatment cycles and granulocyte colony-stimulating factor (G-CSF) support. Results: No differences in neutropenia or febrile neutropenia were demonstrated. However, thrombocytopenia was significantly increased with FEC-DG treatment (2.0 vs. 0.5 %, p < 0.001), as was leukopenia (64.1 vs. 58.5 %, p < 0.001). With FEC-DG significantly more G-CSF support in cycles 4 to 6 (FEC-DG: 57.8 %, FEC-D: 36.3 %, p < 0.001) was provided. Transaminase elevation was significantly more common with FEC-DG (SGPT: 6.3 %, SGOT: 2 %), whereas neuropathy (1.2 %), arthralgia (1.6 %) and bone pain (2.6 %) were more common using FEC-D. Dose reductions > 20 % (4 vs. 2.4 %) and postponement of treatment cycles (0.9 vs. 0.4 %) were significantly more frequent in the FEC-DG arm. Eight deaths occurred during treatment in the FEC-DG arm and four in the FEC-D arm. Conclusion: The addition of gemcitabine increased hematological toxicity and was associated with more dose reductions and postponements of treatment cycles.

Lack of effect of adjuvant chemotherapy on the elimination of single dormant tumor cells in bone marrow of high-risk breast cancer patients.

PURPOSE: There is an urgent need for markers that can predict the efficacy of adjuvant chemotherapy in patients with solid tumors. This study was designed to evaluate whether monitoring of micrometastases in bone marrow can predict the response to systemic chemotherapy in breast cancer. PATIENTS AND METHODS: Bone marrow aspirates of 59 newly diagnosed breast cancer patients with either inflammatory (n = 23) or advanced (> four nodes involved) disease (n = 36) were examined immunocytochemically with the monoclonal anticytokeratin (CK) antibody A45-B/B3 (murine immunoglobulin G(1); Micromet, Munich, Germany) before and after chemotherapy with taxanes and anthracyclines. RESULTS: Of 59 patients, 29 (49.2%) and 26 (44.1%) presented with CK-positive tumor cells in bone marrow before and after chemotherapy, respectively. After chemotherapy, less than half of the previously CK-positive patients (14 of 29 patients; 48.3%) had a CK-negative bone marrow finding, and 11 (36. 7%) of 30 previously CK-negative patients were CK-positive. At a median follow-up of 19 months (range, 6 to 39 months), Kaplan-Meier analysis of 55 assessable patients revealed a significantly reduced overall survival (P =.011; log-rank test) if CK-positive cells were detected after chemotherapy. In multivariate analysis, the presence of CK-positive tumor cells in bone marrow after chemotherapy was an independent predictor for reduced overall survival (relative risk = 5.0; P =.016). CONCLUSION: The cytotoxic agents currently used for chemotherapy in high-risk breast cancer patients do not completely eliminate CK-positive tumor cells in bone marrow. The presence of these tumor cells after chemotherapy is associated with poor prognosis. Thus, bone marrow monitoring might help predict the response to systemic chemotherapy.

Effects of tamoxifen and octreotide LAR on the IGF-system compared with tamoxifen monotherapy.

The insulin-like growth factor (IGF)-system was evaluated in 150 breast cancer patients participating in a randomised phase III trial comparing octreotide pamoate and tamoxifen with tamoxifen+placebo. Alterations in the IGF-system in the two treatment arms and individual changes with respect to outcome were compared. Serum IGF-I and -II, free IGF-I, and insulin-like growth factor binding protein 1-3 (IGFBP1-3) were measured by radioimmmunoassay (RIA)/immunoradiometric assay (IRMA) and IGFBPs by Western ligand blots (WLB) before and during treatment. Combined treatment caused a higher increase in IGFBP-1 and larger suppression of total and free IGF-I, IGF-II, and IGFBP-3 (P<0.01 for all), but less suppression of IGFBP-2 (P<0.05) compared with tamoxifen monotherapy. An increase in IGFBP-2 25% was associated with decreased progression-free survival (PFS) in the total patient population and combined treatment group. Similar response rates and time to progression in the treatment arms suggests moderate suppression of circulating IGF-I has no influence on clinical outcome.

Isolated tumor cells in the bone marrow (ITC-BM) of breast cancer patients before and after anthracyclin based therapy: influenced by the HER2- and Topoisomerase IIalpha-status of the primary tumor?

PURPOSE: The presence of isolated tumor cells in the bone marrow (ITC-BM) is an independent prognostic factor in all stages of breast cancer. Both the expression/amplification of human epithelial growth factor receptor 2 (HER2) and Topoisomerase IIalpha (TOP IIa), a key enzyme of DNA replication and main target of anthracyclins, in breast cancer tissue seem to have predictive value regarding the effectiveness of systemic therapies. METHODS: To investigate the correlation between these factors and their influence on clinical outcome, tumor tissue of 54 patients who were screened for ITC-BM before and after anthracyclin-based chemotherapy (abCTX) was examined for HER2 and TOP IIa by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). RESULTS: By IHC, 31% of the tumors showed positive for HER2 (2+/3+), 14.6% were amplified in FISH. TOP IIa expression (>50%) was found in 13/53 patients (25%), FISH was positive in 5/47 cases (11%). TOP IIa amplification was not seen in cases without HER2 amplification, five of the seven HER2 amplified cases also were amplified for TOP IIa (71% co-amplification). Forty-three patients had adjuvant, seven neo-adjuvant, four palliative abCTX. ITC-BM were present in 24% of patients before and 31% after CTX. Patients with HER2 (IHC, P = 0.29) and TOP IIa (FISH, P = 0.16) positive tumors tended to stay or become negative in BM status after abCTX and vice versa. After a median follow-up of 44 months (6-127), none of the factors reached significance for overall survival. Yet, patients with HER2 (P = 0.16) and TOP IIa (P = 0.09) positive tumors showed a trend towards prolonged disease-free survival. Remarkably, none of the TOP IIa FISH-positive patients developed distant metastases (P = 0.099) or died (P = 0.19) after CTX so far. CONCLUSIONS: HER2- and TOP IIa positivity seem to improve the effect of abCTX. The combination of the prognostic value of ITC-BM and the predictive capacity of HER2 and TOP IIa could help to stratify patients for certain therapies. The direct examination of those factors on ITC-BM is the focus of ongoing studies.