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We have measured the threshold center-of-mass kinetic energy for knocking out a single carbon atom from C 60 − in collisions with He. Combining this experimental result with classical molecular dynamics simulations, we determine a semi-empirical value of 24.1 ± 0.5 eV for the threshold displacement energy, the energy needed to remove a single carbon atom from the C60 cage. We report the first observation of an endohedral complex with an odd number of carbon atoms, He@C 59 − , and discuss its formation and decay mechanisms.

We have observed significant differences in the fragmentation patterns of isomeric Polycyclic Aromatic Hydrocarbon (PAH) cations following collisions with helium atoms at center-of-mass energies around 100 eV. This is in contrast to the situation at other collision energies or in photo-absorption experiments where isomeric effects are very weak and where the lowest-energy dissociation channels (H- and C2H2-loss) domihate in statistical fragmentation processes. In the 100 eV range, non-statistical fragmentation also competes and is uniquely linked to losses of single carbon atoms (CHx-losses). We find that such CHx-losses are correlated with the ionic ground state energy within a given group of isomers. We present results for three C16H10+, four C18H12+ and five C20H12+ isomers colliding with He. (C) 2015 The Authors. Published by Elsevier B.V.

We have studied the fragmentation of the singly protonated l - and d -forms of enantiomerically pure phenylalanine (Phe), tryptophan (Trp), and methionine (Met) in high-energy collisions with chiral and achiral gas targets. (S)-(+)-2-butanol, racemic (±)-2-butanol, and argon were used as target gases. At center-of-mass frame collision energy of 1 keV, it was found that all of the ions exhibit common fragmentation pathways which are independent of target chirality. For all projectile ions, the elimination of NH 3 and H 2 O + CO were found to be the main reaction channels. The observed fragmentation patterns were dominated by statistically driven processes. The energy deposited into the ions was found to be sufficient to yield multiple fragment ions, which arise from decomposition via various competitive reaction pathways.

Estrogen Receptor 1 (ESR1) aberrations may be associated with expression of estrogen receptor (ER) or progesterone receptor (PgR), human epidermal growth factor receptor-2 (HER2) or Ki-67 labeling index and prognosis.ESR1 was assessed in 1129 (81%) of 1396 postmenopausal Danish women with early breast cancer randomly assigned to receive 5 years of letrozole, tamoxifen or a sequence of these agents in the Breast International Group 1-98 trial and who had ER ≥ 1% after central review.By FISH, 13.6% of patients had an ESR1-to-Centromere-6 (CEN-6) ratio ≥ 2 (amplified), and 4.2% had ESR1-to-CEN-6 ratio0.8 (deleted). Deletion of ESR1 was associated with significantly lower levels of ER (P0.0001) and PgR (P = 0.02) and more frequent HER2 amplification. ESR1 deletion or amplification was associated with higher-Ki-67 than ESR1-normal tumors. Overall, there was no evidence of heterogeneity of disease-free survival (DFS) or in treatment effect according to ESR1 status. However, significant differences in DFS were observed for subsets based on a combination of ESR1 and HER2 status (P = 0.02).ESR1 aberrations were associated with HER2 status, Ki-67 labeling index and ER and PgR levels. When combined with HER2, ESR1 may be prognostic but should not be used for endocrine treatment selection in postmenopausal women with endocrine-responsive early breast cancer.

The interaction of slow ions ( v ∼ 0.4 a.u. ) with a small polycyclic aromatic hydrocarbon, namely anthracene (C 14 H 10 ), is studied in the gas-phase either with the isolated molecule or with a pure cluster target. We discuss the ionization and fragmentation of the molecule with respect to the projectile charge state, i.e. for singly charged He + ions and for multiply charged Xe 20+ ions. For the isolated C 14 H 10 , single or multiple ionization of the molecule occurs under ion impact. The (multi) cation relative yields are compared with those obtained by other ionization methods (electron and fs-laser). The molecular dissociation occurs by loss of hydrogen and small hydrocarbon molecules, leading to the formation of C n H x cations. The interaction of Xe 20+ with C 14 H 10 clusters gives surprising results, i.e. the emission of hotter monomer compared to the interaction with He + .

We have tested the ion-storage capabilities of the compact triple-electrode electrostatic ion-beam trap, ConeTrap, down to cryogenic temperatures. The low-temperature operation of this electrostati ...

Study aim: Amenorrhoea is a common side-effect to chemotherapy of premenopausal women. We examine the association between chemotherapy-induced leucopaenia and the development of amenorrhoea in premenopausal women with breast cancer. Materials and methods: in a multi-centre, randomised, controlled study, 1016 premenopausal women received seven series of FEC (F: fluorouracil, E: epirubicin and C: Cyclophosphamide) for early stage breast cancer. In the first series, all patients received standard dose (F: 600 mg/m(2), E: 60 mg/m(2) and C: 600 mg/m(2)). Patients with leukocyte nadir 1.0-1.9 x 10(9)/l continued with standard dose for the remaining six series (STANDARD(REGISTERED), n = 279). Patients with leukocyte nadir >= 2 x 10(9)/l were randomised to standard (STANDARD(RANDOMISED), n = 373) or increased (TAILORED, n = 364) dose of E and C. After each series, leukocyte nadir was evaluated. Absent bleeding after the 5th-7th series of FEC was interpreted as amenorrhoea. Results: The risk of amenorrhoea increased with age. In age-stratified analysis of the STANDARD groups (equal dose, different initial leukocyte nadir) low leukocyte nadir was associated with amenorrhoea for patients in the age-group 25-39 years (P = 0.010). In age-stratified analysis in the randomised groups (different doses, same initial leukocyte nadir) a dose related increased risk of amenorrhoea was found for age-groups 25-39 (RR: 1.15, 95% confidence interval (CI): 1.06-1.24) and 40 44 years (RR:1.21, 95% CI: 1.001-1.47). Conclusion: Age is the most important risk factor of amenorrhoea after FEC chemotherapy. However, for younger patients, lower leukocyte nadir in response to STANDARD FEC treatment or increased doses of C and E were associated with increased risk of amenorrhoea. (C) 2009 Elsevier Ltd. All rights reserved.

Purpose A number of prospective studies have shown that adjuvant CEF significantly improves disease-free and overall survival as compared to CMF in breast cancer patients. Our aim was to determine whether the benefit of epirubicin versus methotrexate differs according to TIMP-1 tumour cell immunoreactivity. Experimental design Tissue micro arrays from 647 patients randomly assigned to CMF or CEF in DBCG trial 89D were included. The primary end-point was invasive disease-free survival (IDFS). A central assessment of tissue inhibitor of metalloproteinases 1 (TIMP-1) status was performed using immunohistochemistry (IHC). Tumours were regarded as TIMP-1 positive if epithelial breast cancer cells were stained using the anti-TIMP-1 monoclonal antibody VT7. Results By central assessment 75% of tumours were classified as tumour cell TIMP-1 positive. Among CEF-treated patients, individuals with TIMP-1 negative tumours had a significant longer IDFS than patients with TIMP-1 positive tumours (p = 0.047). The multivariate Cox regression analysis of IDFS showed that CEF was superior to CMF among patients with TIMP-1 negative tumours (hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.31–0.84, p = 0.0085), while no significant difference could be demonstrated among patients with TIMP-1 positive tumours (HR = 0.88; 95% CI: 0.68–1.13, p = 0.32). A non-significant TIMP-1 status (positive or negative) versus treatment (CMF or CEF) interaction was detected for IDFS (p = 0.06) and OS (p = 0.21). Conclusion Lack of TIMP-1 tumour cell immunoreactivity seems to predict a favourable effect of epirubicin-containing adjuvant therapy in primary breast cancer. However, an independent study is awaited to validate the potential predictive value of TIMP-1 immunoreactivity.

The tumor level of TIMP-1 has been suggested as a new prognostic marker in breast cancer. The purpose of this study was to investigate whether TIMP-1 also carries prognostic information when measured in blood as this is a much more preferable material compared with tumor extracts. Using ELISA, TIMP-1 was measured in prospectively collected preoperative plasma and serum samples from 519 patients with primary breast cancer, and the measurements were related to patient outcome. The median age of the patients was 58 years (range, 38–80 years), and the median follow-up time was 1043 days (range, 300–1630 days). Plasma and serum TIMP-1 measurements correlated significantly with each other with a Pearson correlation coefficient of 0.75 (p

Udgivelsesdato: 2007-Mar We compared the efficacy of CEF (cyclophosphamide, epirubicin, and fluorouracil) against CMF (cyclophosphamide, methotrexate, and fluorouracil) in moderate or high risk breast cancer patients. We randomly assigned 1224 patients with completely resected unilateral breast cancer to receive nine cycles of three-weekly intravenous CMF or CEF. Patients were encouraged to take part in a parallel trial comparing oral pamidronate 150 mg twice daily for 4 years versus control (data not shown). Substitution of methotrexate with epirubicin significantly reduced the unadjusted hazard for disease-free survival (DFS) by 16% (hazard ratio 0.84; 95% CI; 0.71-0.99) and for overall survival by 21% (hazard ratio 0.79; 95% CI; 0.66-0.94). The risk of secondary leukaemia and congestive heart failure was similar in the two groups. Overall CEF was superior over CMF in terms of DFS and OS in patients with operable breast cancer without subsequent increase in late toxicities

In early breast cancer, adjuvant therapy significantly reduces the risk of recurrence after complete surgical resection of the tumor mass. For over a decade, 5 years of adjuvant endocrine therapy with the selective estrogen receptor modulator tamoxifen has been the gold standard in hormone-receptor-positive (HR+) disease. Despite therapy with tamoxifen, relapses still occur, and the rate of relapse is particularly high in the first 2–3 years after surgery. More effective therapies are urgently required to prevent these relapses, particularly in patients with higher-risk disease. The third-generation aromatase inhibitors (AIs), letrozole, anastrozole and exemestane, have shown greater efficacy than tamoxifen, with comparable tolerability, in large, randomized, phase III trials in the early adjuvant setting. On the basis of these findings, AIs are now displacing tamoxifen as the preferred adjuvant endocrine therapy for HR+ early breast cancer in postmenopausal women. Two treatment strategies have been used to investigate AI efficacy in the early adjuvant setting, both with 5 years’ tamoxifen as the comparator: upfront AI for 5 years, or switching to an AI after completing between 2 and 3 years of tamoxifen. When given upfront, anastrozole (ATAC trial) and letrozole (BIG 1-98 trial) have been shown to significantly improve disease-free survival compared with tamoxifen. Letrozole also significantly reduced the risk of distant recurrence, a well-recognized predictor of breast cancer death. Indirect comparisons suggest that these two AIs may not be clinically equivalent, but a direct comparison of letrozole and anastrozole in a prospective, randomized trial is required to prove whether these two AIs do differ clinically. Switching to exemestane or anastrozole therapy after 2–3 years of tamoxifen has also been shown to significantly reduce the risk of relapse compared with 5 years of tamoxifen therapy. However, in these trials, randomization and/or analyses were initiated at the time of switching therapy, including only patients who remained disease-free at this time, thus excluding patients with higher-risk disease who had experienced early relapse, and selecting a more favorable patient population. Trials comparing upfront AIs with the sequential approaches are ongoing: BIG 1-98 and amended TEAM. Of note BIG 1-98 is the only trial to include both switching strategies: tamoxifen followed by letrozole and letrozole followed by tamoxifen. Trials in the early adjuvant setting have revealed that AIs are generally well tolerated: side effects are predictable and manageable. Although further studies are required to determine the optimum treatment strategy and duration of AI therapy, the third-generation AIs are proving highly effective agents in the treatment of HR+ early breast cancer, and bring into question the validity of tamoxifen as the gold standard for adjuvant therapy. Recently updated international guidelines now recommend that early adjuvant therapy should include an AI.

Electron capture processes were studied in glancing collisions between multiply charged C60q+ ions and neutral C60 molecules at low collision energies where nuclear stopping dominates the interaction (typical energy: 10 keV; velocity v = 0.024 a .u . ). In addition, clusters of fullerenes were multiply ionized in collisions with highly charged slow ions and their fragmentation spectra were measured by applying multi-coincidence techniques in a second, separate experiment. Through the first experiment we show that non-fragmenting electron capture collisions do not produce free electrons in C60q+–C60 collisions (q = 1–5), i.e., the cross sections for transfer ionization processes are negligible in this charge state regime. This is in contrast to the case of atomic projectile ions where transfer ionization processes, as e.g., Cq+ + C60 → C(q−r)+ + C60r+ → C(q−r+1)+ + C60r+ + e−, are strong for q > 2. These results are rationalized by means of the classical over-the-barrier model for electron transfer between two C60 molecules, or between an atomic ion and a C60 molecule, where the molecules are modeled as conducting spheres. Further, the same model may also be used as a basis for understanding the present observations of limitations in the maximum numbers of charges, which might be transferred in non-fragmenting C60q+–C60 collisions (q/2 for even q and (q + 1)/2 for odd q) and in Cq+–C60 collision (here up to q charges may be transferred). In the same experiment, we have further measured scattering angles, θ, and energy losses, ɛ, for the fullerene projectiles in C60q+–C60 collisions and we have found low values for both θ and ɛ, which, however, increase with the number of C2-units lost from the projectile fullerene in electron capture collisions. The critical distances for electron transfer which are deduced from the C60q+–C60 collision experiment and the Zettergren model are then used to explain the high charge mobility between the individual C60 molecules in charged (C60)n van der Waal's clusters of fullerenes, which we observe in the second experiment.

We have performed an experimental study of highly charged clusters of fullerenes produced in slow collisions with highly charged ions. Collision products are analysed with respect to their mass to charge ratio and their initial kinectic energy by a linear time-of-flight mass spectrometer. An event-by-event data registration mode allows to study the correlation between the different detected fragments. In this paper, we focus on the kinetic energy releases (KER) in the fragmentation of charged dimers of fullerenes. The results are compared with theoretical values obtained from the conducting sphere model.

Using the unique combination of the high-quality ion beams available in the heavy-ion storage ring CRYRING at the Manne Siegbahn Laboratory, Stockholm and our COLTRIMS (cold target recoil-ion-momentum spectroscopy) setup with a pulsed extraction system we have investigated the recoil-ion-momentum distributions for transfer ionization in p–He collisions at energies up to 5.8 MeV. This technique allows us to determine the separate contribution to the cross section from the Thomas p–e–e scattering mechanism. Unlike the situation at lower collision energies we find that the cross section follows the expected asymptotic v −11 scaling.

Correlated many-particle dynamics in Coulombic systems, which is one of the unsolved fundamental problems in AMO-physics, can now be experimentally approached with so far unprecedented completeness and precision. The recent development of the COLTRIMS technique (COLd Target Recoil Ion Momentum Spectroscopy) provides a coincident multi-fragment imaging technique for eV and sub-eV fragment detection. In its completeness it is as powerful as the bubble chamber in high energy physics. In recent benchmark experiments quasi snapshots (duration as short as an attosecond) of the correlated dynamics between electrons and nuclei have been made for atomic and molecular objects. This new imaging technique has opened a powerful observation window into the hidden world of many-particle dynamics.

Several studies have demonstrated an association between high tumor tissue levels of total tissue inhibitor of metalloproteinases-1 (TIMP-1) and a poor prognosis of primary breast cancer patients. In the present study we investigated whether measurements of the uncomplexed fraction of TIMP-1 added prognostic information to that already obtained from total TIMP-1. We measured the uncomplexed fraction of TIMP-1, using a thoroughly validated ELISA specific for this fraction, in 341 tumor tissue extracts obtained from patients with primary breast cancer. These measurements were related to previously performed measurements of total TIMP-1 as well as to patient outcome. The observation time was 8.3 years (range, 7.3-11.3 years). During this period 136 patients died, and 153 patients experienced recurrence of disease. Cox regression analysis of recurrence-free survival (RFS) suggested that a score based on both uncomplexed and total TIMP-1, reflecting the tumor level of TIMP-1/MMP complexes, would be a more precise estimate of prognosis than total TIMP-1 alone. Univariate survival analysis showed a highly significant relationship between high values of the score and poor outcomes for RFS (p = 0.0002; hazard ratio = 2.7; 95% confidence interval, 1.5-4.8). Similar results were found for overall survival (p = 0.0001; hazard ratio = 3.3; 95% confidence interval, 1.8-6.3). Multivariate analysis of RFS and overall survival demonstrated that the score was significant including the classical prognostic factors used in breast cancer (p < 0.0001). The present study raises the hypothesis that it is the tumor level of TIMP-1/MMP complexes (i.e. activated matrix metalloproteinases) rather than TIMP-1 itself that determines prognosis, supporting the use of the combined score and not only total TIMP-1 in stratification of breast cancer patients.

A systems model has been developed to support the process of choosing the optimal level of farm mechanisation in terms of technical capability. The optimisation model is a non-linear programming model implemented by using the programming software suite General Algebraic Modelling System (GAMS). It is based upon a least-cost concept involving all expected fixed and variable costs (including timeliness costs) for a particular farm size and crop plan. The output from the model is the sizing of each machine, and also the tractor power and number of tractors required. The effective work rates of the machinery sets and the duration in nominal time for performing each operation are also shown. The selection is based upon a farm-oriented matrix involving various types of constraints, such as available man-hours, available machine- and tractor-hours, timeliness and workability of operations, agronomic window of operations, and sequence of operations. The model was tested and verified for its operational behaviour using real farm data. Comparisons of the optimised machinery requirements with the actual machinery present on a case-study farm showed generally good agreement, although there were some significant differences, suggesting that some of the actual machines were not sized optimally.

Analyses of data from cancer registries have shown a 10% unit difference in 5-year relative survival between Danish and Swedish patients with breast cancer. This study investigates the effect of age and patho-anatomic variables on this survival difference. Hospital records were collected for women over 40 years of age diagnosed in 1989 or 1994 in east Denmark and south Sweden; patho-anatomical variables and survival were compared between 2289 Danish and 1715 Swedish women. Tumours were smaller, node-negative axillae more frequent and well-differentiated tumours almost 10% more frequent in Sweden. A superior 5-year relative survival in Sweden was found in the 50- to 79-year age group. The adjusted hazard rate ratio between countries was 1.7 in 1989 and 1.3 in 1994. Conditional survival after surviving the first 5 years was similar for the two countries. Adjusting for patho-anatomical variables reduced but did not eliminate the higher risk of death among the Danish patients. Higher population death rates could explain some but not all of the residual elevated risk for Danish women.

The Danish Breast Cancer Cooperative Group (DBCG) was established in 1977 with the aim to ensure optimal breast cancer diagnostics and therapeutic modalities on a nationwide basis. DBCG was organized in such a way so it represents a broad interdisciplinary collaboration with established clinical databases and biobanks. This review summarizes the infrastructures, such as those of the DBCG, that are required to facilitate translational research studies aiming at further diagnostic and therapeutic improvements through interactions directed at prevention, early diagnosis, and treatment of primary breast cancer.

A woman's risk of developing breast cancer is closely related to reproductive factors. Whereas the etiological importance of reproductive factors is well described, less is known about the prognostic influence of these factors. The prognostic effect of childbearing before, around, and after diagnosis is reviewed based on the literature and on studies from Danish Breast Cancer Cooperative Group, DBCG. In women with breast cancer overall number of childbirths is found to be without prognostic importance. Women with early primary childbirth seem to have an inferior prognosis compared to women who postpone childbearing. It is generally accepted that early first childbirth is associated with reduced risk of developing breast cancer. Thus, it is proposed that women who develop breast cancer despite an early first delivery represent a selected group of patients with particularly aggressive disease. Women diagnosed with breast cancer during pregnancy often present with advanced disease, but pregnancy at time of diagnosis does not seem to be an independent prognostic factor. However, women diagnosed with breast cancer in the first years after childbirth have a significantly reduced survival. It is assumed that these women, due to the physiological changes during pregnancy, experience growth induction of the tumours during the preclinical stage. In contrast, there is no evidence that pregnancy after breast cancer treatment has a negative influence on prognosis.

The goal of endocrine therapy in breast cancer is to block the action of estrogen on the tumor cells either by inhibiting estrogen from binding to the specific estrogen receptor or by inhibiting its synthesis. Tamoxifen, a selective estrogen receptor modulator, is the standard endocrine treatment for hormone receptor-positive breast cancer, both in the adjuvant and metastatic settings. Tamoxifen inhibits the binding of estrogen to the receptor, resulting in inhibition of hormone action. However, as tamoxifen is also weakly estrogenic, it may not be optimally effective and increases the risk of endometrial cancer and stroke. Furthermore, patients may be refractory or may become resistant to tamoxifen treatment. Since aromatase inhibitors (AI) block the synthesis of estrogen and have no intrinsic estrogenic activity, they have the potential to be more effective than tamoxifen. Their different mechanism of action and chemical structures may also circumvent tamoxifen resistance. Consequently, AIs are currently being evaluated as an alternative to tamoxifen treatment. A preclinical model has recently been developed to compare the efficacy of AIs and antiestrogens in different treatment schemes and to assist in the design of clinical trials. Current studies with the MCF-7Ca xenograft model are exploring the effects of combination and sequential therapy on tumor growth. The efficacy of AIs in the treatment of hormone receptor-positive breast cancer was first demonstrated in five multicenter second-line trials enrolling several hundreds of postmenopausal patients with metastatic breast cancer who had failed tamoxifen treatment. More recently, anastrozole demonstrated efficacy at least equivalent to that of tamoxifen in first-line randomized, phase III clinical trials in postmenopausal women with hormone receptor-positive or unknown metastatic breast cancer, whereas letrozole demonstrated superiority. The steroidal AI exemestane is currently under evaluation. Letrozole is the only AI to have been studied in a randomized, phase III trial in the neoadjuvant setting. In this trial, more patients underwent breast-conserving surgery with letrozole than with tamoxifen. Smaller phase II studies also suggest that both anastrozole and exemestane are active in the neoadjuvant setting. Because neoadjuvant trials permit temporal sampling of breast tissue, substudies in the phase III trial with letrozole have examined the impact of such biomarkers as estrogen receptor, progesterone receptor and epidermal growth factor receptor family members, HER-1 and HER-2, on patient response. AIs are currently under evaluation in the adjuvant setting, and preliminary results of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial have been reported. AIs have proven as safe as tamoxifen in trials in patients with metastatic breast cancer. Ongoing clinical trials in the adjuvant setting include companion studies of end-organ effects, particularly bone metabolism and lipid metabolism evaluations. Quality-of-life assessments are also parts of major clinical trials. A head-to-head quality-of-life assessment of anastrozole compared with letrozole demonstrated patient preference for letrozole. These assessments also clearly indicated the eagerness of patients to participate actively in treatment decisions

The purpose of the study was to investigate whether baseline quality of life (QoL) and changes in QoL scores from baseline are prognostic for time to progression (TTP) and/or overall survival (OS) in patients with advanced breast cancer receiving docetaxel (T) or sequential methotrexate and 5-fluorouracil (MF). QoL was assessed at baseline and before each treatment using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). Survival curves and probabilities were estimated using the Kaplan-Meier technique. The Cox proportional hazards regression model was used for both the univariate and multivariate analyses to explore relationships between baseline QoL variables and TTP, as well as OS. In the univariate analysis, more severe pain and fatigue at baseline were predictive for a shorter OS; global QoL, physical functioning and appetite loss had a borderline significance (P=0.0130 for global QoL; P=0.0256 for physical functioning: P=0.0149 for appetite loss). World Health Organization (WHO) performance status was significantly predictive for OS. In the multivariate analysis, more severe pain at baseline was predictive for a shorter OS. In contrast, baseline QoL had no prognostic value for the duration of TTP. QoL change scores from baseline QoL predicted neither OS nor TTP. Our findings suggest that while QoL measurements are important in evaluating patients' QoL, they have no great importance in predicting primary clinical endpoints such as TTP or OS in advanced breast cancer patients.

The purpose of this study was to investigate the association between tumor tissue levels of total tissue inhibitor of metalloproteinases-1 (TIMP-1) and prognosis in patients with primary breast cancer and to analyze whether measurement of TIMP-1 in tumor extracts added prognostic information to that obtained from measurements of urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 (PAI-1). An established sandwich enzyme-linked immunosorbent assay was thoroughly validated for the measurement of total TIMP-1 in tumor tissue extracts and used to determine levels of total TIMP-1 in 341 detergent-extracted tumor tissue samples from patients with primary breast cancer. The median age of the patients was 56 years (range, 29-75 years), and 164 were lymph node-negative, and 177 were lymph node-positive. The median follow-up time of the patients was 8.5 years (range, 7.3-11.3 years), and during follow-up 153 patients experienced recurrence of disease, and 136 patients died. In univariate survival analysis, we found a significant association between tumor tissue TIMP-1 level and both shorter recurrence-free survival (p = 0.0004) and shorter overall survival (p = 0.03). In multivariate survival analysis, higher tumor tissue TIMP-1 levels significantly and independently predicted shorter recurrence-free survival (p0.05, hazard ratios1, comparing quartiles II-IV with I). In addition, we found that measurement of TIMP-1 levels added prognostic information to that obtained from measurement of PAI-1. In conclusion, high levels of TIMP-1 in tumor tissue extracts are significantly associated with a poor prognosis in patients with primary breast cancer. Furthermore TIMP-1 adds prognostic information to that obtained from PAI-1. However, further validation in independent data sets is needed.

The aim of this phase 11 study was to evaluate the efficacy and toxicity of two regimens of ifosfamide in metastatic soft tissue sarcoma patients given as first- and second-line chemotherapy. Two different schedules of ifosfamide were investigated in a randomised manner: Ifosfamide was given either at a dose of 5 g/m(2) over 24 h (5 g/m(2)/l day), every 3 weeks or at a dose of 3 g/m(2) per day, administered over 4 h on three consecutive days (3 g/m(2)/3 days), every 3 weeks. Both schedules were given as first-line or second-line chemotherapy. A total of 182 patients was entered, 103 in first- and 79 in second-line, of whom 8 patients were ineligible, 5 in the first- and 3 in the second-line study. Most patients had a leiomyosarcoma, 46 of the 98 in the first-line and 34 of the 76 in the second-line. The two study arms were well balanced in both the first- and second-lines with respect to sex, age and performance status. In first-line treatment, 5 g/m(2)/l day yielded five partial responses (PR) (Response Rate (RR) 10%), versus 12 PR (RR 25%) for the 3 g/m(2)/3 days. As second-line treatment, the 24-h infusion yielded: one CR and one PR (RR 6%) and the 3-day schedule one CR and two PR (RR 8%). Survival did not differ between the two regimens. The major World Health Organization (WHO) grade 3 and 4 toxicities encountered were: leucopenia in 19% of all courses in the first-line and 32% in the second-line with the 5 g/m(2)/l day, while for the 3 g/m(2)/3 days schedule the rates were 57 and 63% respectively. Grade 3 or 4 infections were seen in 4% of patients treated with 5 g/m(2)/l day first-line and 10% of patients given 3 g/m(2)/3 days, both as first- and second-lines. No such infections were seen in patients receiving 5 g/m(2)/l day as second line treatment. In advanced soft-tissue sarcomas in the first-line, ifosfamide 3 g/m(2), given over 4 h on three consecutive days, is an active regimen with acceptable toxicity while the 5 g/m(2) over 24 hours schedule resulted in a disappointing response rate. (C) 2002 Elsevier Science Ltd. All rights reserved.

We have developed a very simple and compact fully electrostatic ion storage device. It consists of only three electrodes: two conical and one central cylindrical. This simple setup works as two focusing electrostatic mirrors forming a resonator-like structure and thereby confining the ions. We present the design and show the first test results demonstrating an ion-storage lifetime in the 100 ms-range at modest vacuum conditions. Storage lifetimes in the order of minutes are foreseen when UHV conditions are introduced.

Aims: We investigated whether menstrual cycle dependent variations in prognostic factors are detectable in malignant breast tissue. Methods: Since 1977 the Danish Breast Cancer Cooperative Group has collected population-based information about primary clinical data, treatment regimens and follow-up status on Danish women with breast cancer. Information about last menstrual periods prior to surgery was obtained from files recorded at the time of admission for primary surgery. Included in this study were 1060 patients self-reported to be regularly menstruating and with a menstrual period within 6 weeks of surgery and who were operated in a single-step procedure. None of the patients were current users of exogenous hormones at the time of surgery. Variations of prognostic factors throughout the menstrual cycle were evaluated. Results: Overall, no significant correlation between endogenous hormone fluctuations and oestrogen receptor (ER) status and progesterone receptor (PgR) status were found. Furthermore, we observed no cycle-dependent variation for mitotic index, lymph node involvement or tumour size. Conclusions: The classical prognostic factors in breast cancer did not differ significantly throughout the menstrual cycle in the present study.

The aim of this study was to compare the efficacy and tolerability of docetaxel to methotrexate and 5-fluorouracil in advanced breast cancer after anthracycline failure. A randomised multicentre trial was conducted in 283 patients with advanced breast cancer who had failed previous anthracycline treatment. Docetaxel at a dose of 100 mg/m2 every 3 weeks (n = 143) was compared with sequential methotrexate and 5-fluorouracil (MF; n = 139) given at day 1 and 8 every 3 weeks at dosages of 200 mg/ m2 and 600 mg/m2, respectively. After progression, crossover to the alternative treatment group was recommended. There was a significantly higher overall response rate in the docetaxel 42% (CR 8% + PR 34%) than in the MF arm 21% (CR 3% + PR 18%) (P < 0.001). The median time to progression (TTP) was 6.3 months in the docetaxel arm and 3.0 months in the MF arm (P < 0.001). Docetaxel also had a significantly higher response rate of 27% following crossover compared with MF (12%). Significantly more side-effects (leucopenia, infections, neuropathy, oedema, asthenia, skin, nail changes, alopecia) were seen in the docetaxel than in the MF group. However, grade 3 and 4 side-effects were infrequent with both drugs, with the exception of fatigue, alopecia and infections. Median overall survival (OS) including crossover phase was 10.4 months in the docetaxel and 11.1 months in the MF arm (P = 0.79). Based on the response rate and the primary endpoint of TTP, docetaxel is superior to sequential methotrexate and 5-fluorouracil in advanced breast cancer after anthracycline failure.

Breast cancer and its treatment have been associated with psychological morbidity. In this study our aim was to quantify the excess anxiety and depression resulting from breast cancer. We compared 538 newly diagnosed breast cancer patients at low risk of recurrence (87.0% responded) to 872 women randomly selected from the Danish general population (69.7% responded) using the Hospital Anxiety and Depression Scale (HADS). Contrary to expectations, the proportions classified as “cases” of anxiety and depression were not significantly different in the two groups. The breast cancer patients’ mean HADS scores were significantly lower than those in the general population sample (anxiety, P = 0.021; depression, P

We have determined absolute attenuation and electron capture cross sections in ∼100 keV collisions between atomic ions of moderate charge states (He + , He 2+ , Ar 2+ , Ar 3+ , Ar 4+ , Xe 2+ , Xe 3+ , Xe 4+ ) and C 60 molecules in the gas phase. The measured cross-sections support previous findings of the charge dynamics within C 60 from electron capture experiments with higher ionic charges. For a non-negligible fraction of the capture events we observed substantial ionic energy loss (≤2 keV), which is ascribed to collisions where the ion passes through the C 60 molecule. Furthermore, we found that a molecular ion (100 keV CO 2 2+ ) that captures an electron from C 60 can lose similar amounts of energy without dissociating. It is concluded that the predominant contribution to the ionic energy loss comes from electron excitation and ionization.

Amphetamine abuse is widespread and is frequently encountered in general hospital settings. We have recently seen amphetamine-induced transient psychosis associated with severe self-injurious behavior and self-mutilation. In the setting of bizarre and/or severe self-injurious behavior, screening for amphetamines is indicated.

Percutaneous thrombin occlusion of pseudoaneurysms complicating invasive coronary interventions has emerged as a useful therapeutic tool. To facilitate thrombin occlusion and make the procedure even more secure, preinjection of echo contrast medium during duplex ultrasound was tested in 132 patients. Complete and immediate occlusion of the pseudoaneurysm was achieved in 99.2% (131 of 132 patients). No complications related to the injection of thrombin were documented. Contrast-enhanced ultrasound-guided thrombin occlusion was a safe and effective therapeutic option. In aneurysms with complex morphology or multiple cavities, preinjection of contrast medium was helpful for documenting the flow pattern.

This paper shows how the generalized predictive control (GPC) can be extended to non-stationary (time-varying) systems. If the time-variation is slow, then the classical GPC can be used in context with an adaptive estimation procedure of a time-invariant ARIMAX model. However, in this paper prior knowledge concerning the nature of the parameter variations is assumed available. The GPC is based on the assumption that the prediction of the system output can be expressed as a linear combination of present and future controls. Since the Diophantine equation cannot be used due to the time-variation of the parameters, the optimal prediction is found as the general conditional expectation of the system output. The underlying model is of an ARMAX-type instead of an ARIMAX-type as in the original version of the GPC (Clarke, D. W., C. Mohtadi and P. S. Tuffs (1987). Automatica, 23, 137–148) and almost all later references. This implies some further modifications of the classical GPC.

This paper discusses how the control of the flow and the supply temperature in district heating systems can be optimized, utilizing stochastic modelling, prediction and control methods. The main objective is to reduce heat production costs and heat losses in the transmission and distribution net by minimizing the supply temperature at the district heating plant. This control strategy is reasonable, in particular, if the heat production takes place at a combined heat and power (CHP) plant. The control strategy is subject to some restrictions, e.g. that the total heat requirement for all consumers is supplied at any time, and each individual consumer is guaranteed some minimum supply temperature at any time. Another important restriction is that the variation in time of the supply temperature is kept as small as possible. This concept has been incorporated in the program package, PRESS, developed at the Technical University of Denmark. PRESS has been applied and tested, e.g. at Vestkraft in Esbjerg, Denmark, and significant saving potentials have been documented. PRESS is now distributed by the Danish District Heating Association.

Summary Background Current regimens for treatment of distant metastases of soft tissue sarcomas result in response rates of about 25%. Therefore the search for active drugs remains a task for investigationaJ groups. Taxoids offer a new class of cytostatic drugs. Docetaxel has been studied as a second line chemotherapy in advanced soft tissue sarcomas of the adult. Patients and methods In a multi-center non-randomized phase II study docetaxel was administered at a dose of 100 mg/m2 in a 1-hour i.v. infusion q 3 weeks. Results Twenty-nine patients (pts), median age 52 yr, performance status WHO 0: 16 pts, WHO 1: 11 pts, WHO 2: 2 pts, were eligible. One patient had early death due to malignant disease, 1 patient died due to toxicity and progression, 1 pt refused after 1 course. Five partial responses (5/29 – 17%, C.I. 6%–36%) have been observed. Grade ≥3 leucopenia occurred in 76% of patients and grade ≥3 thrombopenia did not occur. Median nadir of neutrophils was 0.23 × 109/1. Episodes of fever and documented infection have been observed in 10 and 5 pts respectively. Anaphylactoid type reactions occurred in 5 patients: ranging from flushing in 5 pts to cardiovascular symptoms in 1 pt. Sensory neurotoxicity was observed in 14 pts grade 1: 10 pts, grade 2: 3 pts, grade 3: 1 pt). Grade 1 motor neurotoxicity was experienced by 3 pts. Skin reactions (pruritus, erythema, urticaria, exfoliation grade 1: 11 pts, grade 2: 7 pts, grade 3: 1 pt, grade 4: 1 pt) in 20 pts, among them 9 patients with nail changes. Peripheral edema and fluid retention has been observed in 12 pts. Conclusion Taxotere has activity in adult soft tissue sarcoma in second line, warranting studies on first line efficacy.

Summary Background An early and reliable diagnosis of metastatic spread has increased interest in serum tumor markers. This study investigated the ability of CA 15.3, CEA, and TPA to identify, predict, and exclude metastases in bone/viscera during adjuvant treatment and follow-up of high-risk breast cancer. Methods Ninety females with high-risk breast cancer were included in the study. Response evaluation was based upon clinical examination, x-rays or histology and elaborated marker criteria. Results During the marker monitoring period, metastases in four patients were confined to skin or lymph nodes, 21 developed metastases to bone/viscera, and 65 females had no evidence of metastases. CA 15.3, CEA, and TPA correctly classified 48%, 10%, and 19% of the patients with metastases in bone/viscera, and 100%, 94%, and 98% without. Following CA 15.3, CEA, and TPA recurrence, 100%, 33%, and 60% of the patients developed metastases in bone/viscera. Metastases in bone(86%)viscera were excluded in 86%, 76%, and 79% of patients without CA 15.3, CEA, and TPA recurrence. Conclusion Only CA 15.3 gave reliable information about recurrence. Metastases in bone(86%)viscera were identified in 10 of the 21 patients with CA 15.3. There was no false-positive CA 15.3 information on the 65 patients without clinical recurrence. The PVneg (86%) indicated that when CA 15.3 did not signal recurrence, metastases to bone(86%)viscera were not likely.

This paper shows how the Generalized Predictive Control (GPC) can be extended to non-stationary (time-varying) systems. If the time-variation is slow, then the classical GPC can be used in context with an adaptive estimation procedure of a time-invariant ARIMAX model. However, in this paper prior knowledge concerning the nature of the parameter variations is assumed available. The GPC is based on the assumption that the prediction of the system output can be expressed as a linear combination of present and future controls, Since the Diophantine Equation cannot be used due to the time-variation of the parameters, the optimal prediction is found as the general conditional expectation of the system output. The underlying model is of an ARMAX type instead of an ARIMAX type as in the original version of the GPC (Clarke et al ., 1987) and almost all later references. This implies some further modifications of the classical GPC.

In a randomised Scandinavian Sarcoma Group study (n = 240) on the effect of postoperative adjuvant doxorubicin in high grade adult soft tissue sarcoma, 26 patients were treated with marginal surgery and postoperative radiotherapy. The protocol dose was 51 Gy in 17 fractions, or equivalent. Local recurrence occurred in 6 patients. Two local failures were geographical misses. Salvage treatment was ultimately successful in 3 of 4 attempted cases. 15 patients had complications, which in 3 cases necessitated amputation. These 3 patients had received the protocol fractionation and doxorubicin. However, other factors possibly responsible for the complication were also present.

A modified version of the linear quadratic Gaussian controller is presented, which is build upon the prediction form of the model. This implies that the controller is more capable of handling non-stationarities, like time-varying model parameters, than the classical type of linear quadratic Gaussian controller, which usually is based on the solution of the Diophantine or the Riccati Equation (in the state-space case). The linear quadratic Gaussian controller is used in a simulation study together with a transfer function model, with time-varying parameters, that describes the relations between supply temperature of the water from a district heating plant and the supply temperature at specific locations in the distribution network. The simulation results show that the variance of the differenced control signal can be reduced drastically without affecting the performance of the controller significantly.

In order to define the term "a node-negative patient", the axillary nodal status at the primary operation for breast cancer was evaluated in 13,851 patients registered by the Danish Breast Cancer Cooperative Group (DBCG). The determinants for node negativity in primary breast cancer were the number of lymph nodes removed and the tumour size. The number of lymph nodes removed should be at least 10 to exclude misclassification of node-positive patients as node negative. There was a strong relationship between tumour size and the percentage of node-negative patients. Another observation was that high rate of node negativity was associated with low histological grade. The age of the patients had no influence on node negativity. Where 10 or more negative lymph nodes were removed, significantly better axillary recurrence-free survival (P less than 0.0001), over-all recurrence-free survival (P less than 0.0001) and survival (P less than 0.005) were found.

The objective of this phase II trial was to assess the therapeutic activity and toxicity of doxorubicin plus ifosfamide in previously untreated patients with advanced soft tissue sarcoma. Treatment was doxorubicin 50 mg/m2 followed by a 24 h infusion of ifosfamide 5 g/m2 plus mesna 2.5 g/m2 repeated every 3 weeks until disease progression or unacceptable toxicity occurred. Of 203 patients entered, 175 were evaluable for response. The response rate was 35% (95% CI 28-42%), with 9% of the patients achieving a complete remission and 26% a partial remission. The median time to progression was 29 weeks for all evaluable patients, and 67, 40 and 28 weeks for complete and partial responders and patients with stable disease, respectively. The median duration of survival was 58 weeks. Myelosuppression was the dose-limiting toxicity, resulting in leukopenia (WHO grade 3 and 4) in 73% of evaluable treatment courses. Other side-effects were rare and usually well manageable.

Forty-four of 50 adult patients with advanced soft-tissue sarcoma who had received previous chemotherapy were evaluable for response after treatment with DTIC. The therapeutic schedule consisted of DTIC 1.2 g/m2 infused over 20 minutes, and repeated every 3 weeks. There were 1 complete and 7 partial remissions (objective activity 18%, 95% C.I. 7%-29%), with a median duration of 8 weeks (range 5-19), with the complete remission lasting 1 yr. Hematologic toxicity was dose-limiting; W.H.O. greater than or equal to 3 values were observed for WBC in 36%, and for platelets in 26% of patients. The non-hematologic toxicity included nausea and vomiting (90%), a flu-like syndrome (49%), diarrhea (35%), pain in the infused vein (28%) and hypotensive episodes (4%). Intermittent high-dose DTIC is active in advanced soft-tissue sarcoma and should be considered for inclusion in combination regimens.