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Fracture induces systemic bone loss in mice and humans, and a first (index) fracture increases the risk of future fracture at any skeletal site more in men than women. The etiology of this sex difference is unknown, but fracture may induces a greater systemic bone loss response in males. Also sex differences in systemic muscle loss after fracture have not been examined. We investigated sex differences in systemic bone and muscle loss after transverse femur fracture in 3-month-old male and female C57BL/6J mice. Whole-body and regional bone mineral content and density (BMC and BMD), trabecular and cortical bone microstructure, muscle contractile force, muscle mass, and muscle fiber size were quantified at multiple time points post-fracture. Serum concentrations of inflammatory cytokines (IL-1s, IL-6, and TNF-α) were measured 1-day post-fracture. One day post-fracture, IL-6 and Il-1B were elevated in fracture mice of both sexes, but TNF-α was only elevated in male fracture mice. Fracture reduced BMC, BMD, and trabecular bone microstructural properties in both sexes 2 weeks post-fracture, but declines were greater in males. Muscle contractile force, mass, and fiber size decreased primarily in the fractured limb at 2 weeks post-fracture and females showed a trend towards greater muscle loss. Bone and muscle properties recovered by 6 weeks post-fracture. Overall, post-fracture systemic bone loss is greater in males, which may contribute to sex differences in subsequent fracture risk. In both sexes, muscle loss is primarily confined to the injured limb and fracture may induce greater inflammation in males. This article is protected by copyright. All rights reserved.

Author(s): Langer, Henning T; Mossakowski, Agata A; Willis, Brandon J; Grimsrud, Kristin N; Wood, Joshua A; Lloyd, Kevin CK; Zbinden-Foncea, Hermann; Baar, Keith | Abstract: BackgroundDesminopathy is a clinically heterogeneous muscle disease caused by over 60 different mutations in desmin. The most common mutation with a clinical phenotype in humans is an exchange of arginine to proline at position 350 of desmin leading to p.R350P. We created the first CRISPR-Cas9 engineered rat model for a muscle disease by mirroring the R350P mutation in humans.MethodsUsing CRISPR-Cas9 technology, Des c.1045-1046 (AGG g CCG) was introduced into exon 6 of the rat genome causing p.R349P. The genotype of each animal was confirmed via quantitative PCR. Six male rats with a mutation in desmin (n = 6) between the age of 120-150 days and an equal number of wild type littermates (n = 6) were used for experiments. Maximal plantar flexion force was measured in vivo and combined with the collection of muscle weights, immunoblotting, and histological analysis. In addition to the baseline phenotyping, we performed a synergist ablation study in the same animals.ResultsWe found a difference in the number of central nuclei between desmin mutants (1 ± 0.4%) and wild type littermates (0.2 ± 0.1%; P l 0.05). While muscle weights did not differ, we found the levels of many structural proteins to be altered in mutant animals. Dystrophin and syntrophin were increased 54% and 45% in desmin mutants, respectively (P l 0.05). Dysferlin and Annexin A2, proteins associated with membrane repair, were increased two-fold and 32%, respectively, in mutants (P l 0.05). Synergist ablation caused similar increases in muscle weight between mutant and wild type animals, but changes in fibre diameter revealed that fibre hypertrophy in desmin mutants was hampered compared with wild type animals (P l 0.05).ConclusionsWe created a novel animal model for desminopathy that will be a useful tool in furthering our understanding of the disease. While mutant animals at an age corresponding to a preclinical age in humans show no macroscopic differences, microscopic and molecular changes are already present. Future studies should aim to further decipher those biological changes that precede the clinical progression of disease and test therapeutic approaches to delay disease progression.

The DBCG89D trial randomized high-risk early breast cancer patients to adjuvant CMF (cyclophosphamide, methotrexate and fluorouracil) or CEF (cyclophosphamide, epirubicin and fluorouracil). Prosigna assays were performed by researchers with no access to clinical data. Time to distant recurrence (DR) was the primary endpoint, time to recurrence (TR) and overall survival (OS) secondary. Among the 980 Danish patients enrolled, Prosigna results were obtained in 686. Continuous ROR score was associated with DR for CMF (adjusted hazard ratio (HR) 1.20, 95% CI 1.09–1.33), and for CEF (HR 1.04, 95% CI 0.92–1.18), Pinteraction = 0.06. DR was significantly longer in CEF compared to CMF treated patients with Her2-enriched tumors (HR 0.58, 95% CI 0.38–0.86), but not in patients with luminal tumors. Heterogeneity of treatment effect was significant for TR and OS. In this prospective-retrospective analysis, patients with Her2-enriched breast cancer derived substantial benefit from anthracycline chemotherapy whereas anthracyclines are not an essential component of chemotherapy for patients with luminal subtypes. The benefit of CEF vs. CMF correlated with increasing ROR Score.

Cannabidiol (CBD) has proven clinical benefits in the treatment of seizures, inflammation, and pain. The recent legalization of CBD in many countries has caused increased interest in the drug as an over-the-counter treatment for athletes looking to improve recovery. However, no data on the effects of CBD on the adaptive response to exercise in muscle are available. To address this gap, we eccentrically loaded the tibialis anterior muscle of 14 rats, injected them with a vehicle (n = 7) or 100 mg/kg CBD (n = 7), and measured markers of injury, inflammation, anabolic signaling, and autophagy 18 hr later. Pro-inflammatory signaling through nuclear factor kappa B (NF-kB) (Ser536) increased with loading in both groups; however, the effect was significantly greater (36%) in the vehicle group (p p = .66). The ribosomal protein S6 phosphorylation (240/244) increased with stimulation (p p = .09). The ubiquitin-binding protein p62 levels were not modulated by stimulation (p = .6), but they were 46% greater in the CBD compared with the vehicle group (p = .01). Although liver weight did not differ between the groups (p = .99) and levels of proteins associated with stress were similar, we did observe serious side effects in one animal. In conclusion, an acute dose of CBD decreased pro-inflammatory signaling in the tibialis anterior without blunting the anabolic response to exercise in rats. Future research should determine whether these effects translate to improved recovery without altering adaptation in humans.

The mechanisms accounting for the loss of muscle function with obesity and type 2 diabetes are likely the result of a combination of neural and muscular factors. One muscular factor that is important, yet has received little attention, is the protein machinery involved in longitudinal and lateral force transmission. The purpose of this study was to compare the levels of force transfer and membrane integrity proteins before and after a 12‐week endurance training program in lean, obese, and obese type 2 diabetic adults. Nineteen sedentary subjects (male = 8 and female = 11) were divided into three groups: Lean (n = 7; 50.3 ± 4.1 y; 69.1 ± 7.2 kg); Obese (n = 6; 49.8 ± 4.1 y; 92.9 ± 19.5 kg); and Obese with type 2 diabetes (n = 6; 51.5 ± 7.9 years; 88.9 ± 15.1 kg). Participants trained 150 min/week between 55% and 75% of VO2max for 12 weeks. Skeletal muscle biopsies were taken before and after the training intervention. Baseline dystrophin and muscle LIM protein levels were higher (~50% p, A 12‐week endurance training regimen has a relatively small effect on the levels of force transfer and membrane integrity proteins of lean, obese and type 2 diabetic individuals. Only dystrophin and muscle ankyrin repeat protein were decreased after training in lean and obese individuals, respectively.

The Copenhagen Breast Cancer Trial (CBCT) randomly assigned patients with early breast cancer to two years of tamoxifen or placebo and we evaluated the effect over the following four decades.Between 1975 and 1978, 327 patients with primary breast cancer were randomly assigned to two years of daily placebo or tamoxifen. Survival statistics was collected from the Danish Civil Registration System.The five-year invasive breast cancer recurrence (BCR) rate was 43.2% in the placebo arm and 31.9% in the tamoxifen arm. Compared with the placebo arm the hazard ratio for a BCR event was 0.73 in the tamoxifen arm (p = .07). With an estimated median follow-up on overall survival of 40.9 years, 154 and 145 patients had died in the placebo and tamoxifen arm, respectively. After adjustment for baseline characteristics a significant reduction in mortality was obtained from tamoxifen (HR 0.79; p = .04).Two years of adjuvant tamoxifen resulted in a sustained reduction in mortality in pre- and postmenopausal high-risk breast cancer patients with long-term follow-up data.

Purpose Administration of anthracycline and taxane therapy in the adjuvant setting is considered a standard for breast cancer. We evaluated a non-anthracycline-based regimen in TOP2A-normal patients. Patients and Methods In this multicenter, open-label, phase III trial, 2,012 women with early TOP2A-normal breast cancer and at least one high-risk factor were randomly assigned to receive six cycles of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (DC) or three cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) followed by three cycles of docetaxel (100 mg/m2; EC-D). The primary end point was disease-free survival (DFS) after a median of 5 years of follow-up. Secondary end points were patient-reported toxicity, overall survival (OS), and distant disease-free survival. Results At a median estimated potential follow-up of 69 months, 5-year DFS was 87.9% (95% CI, 85.6% to 89.8%) in the EC-D arm and 88.3% (95% CI, 86.1% to 90.1%) in the DC arm. There was no significant difference in the risk of DFS events (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00), distant disease-free survival (HR, 1.12; 95% CI, 0.86 to 1.47; P = .40), or mortality (HR, 1.15; 95% CI, 0.83 to 1.59; P = .41) in the intent-to-treat analysis. A significant interaction between menopausal status and treatment group was observed for DFS ( P = .04) but not for OS ( P = .07). Patients with grade 3 tumors derived most benefit from DC, and patients with grade 1 to 2 tumors derived most benefit from EC-D (DFS: interaction P = .02; and OS: interaction P = .03). Patients receiving EC-D reported significantly more stomatitis, myalgia or arthralgia, vomiting, nausea, fatigue, and peripheral neuropathy, whereas edema was more frequent after DC. Conclusion This study provides evidence to support no overall outcome benefit from adjuvant anthracyclines in patients with early TOP2A-normal breast cancer. Purpose Administration of anthracycline and taxane therapy in the adjuvant setting is considered a standard for breast cancer. We evaluated a non-anthracycline-based regimen in TOP2A-normal patients. Patients and Methods In this multicenter, open-label, phase III trial, 2,012 women with early TOP2A-normal breast cancer and at least one high-risk factor were randomly assigned to receive six cycles of docetaxel (75 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks (DC) or three cycles of epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) followed by three cycles of docetaxel (100 mg/m2; EC-D). The primary end point was disease-free survival (DFS) after a median of 5 years of follow-up. Secondary end points were patient-reported toxicity, overall survival (OS), and distant disease-free survival. Results At a median estimated potential follow-up of 69 months, 5-year DFS was 87.9% (95% CI, 85.6% to 89.8%) in the EC-D arm and 88.3% (95% CI, 86.1% to 90.1%) in the DC arm. There was no significant difference in the risk of DFS events (hazard ratio [HR], 1.00; 95% CI, 0.78 to 1.28; P = 1.00), distant disease-free survival (HR, 1.12; 95% CI, 0.86 to 1.47; P = .40), or mortality (HR, 1.15; 95% CI, 0.83 to 1.59; P = .41) in the intent-to-treat analysis. A significant interaction between menopausal status and treatment group was observed for DFS ( P = .04) but not for OS ( P = .07). Patients with grade 3 tumors derived most benefit from DC, and patients with grade 1 to 2 tumors derived most benefit from EC-D (DFS: interaction P = .02; and OS: interaction P = .03). Patients receiving EC-D reported significantly more stomatitis, myalgia or arthralgia, vomiting, nausea, fatigue, and peripheral neuropathy, whereas edema was more frequent after DC. Conclusion This study provides evidence to support no overall outcome benefit from adjuvant anthracyclines in patients with early TOP2A-normal breast cancer.

AIM OF DATABASE: Danish Breast Cancer Cooperative Group (DBCG), with an associated database, was introduced as a nationwide multidisciplinary group in 1977 with the ultimate aim to improve the prognosis in breast cancer. Since then, the database has registered women diagnosed with primary invasive nonmetastatic breast cancer. The data reported from the departments to the database included details of the characteristics of the primary tumor, of surgery, radiotherapy, and systemic therapies, and of follow-up reported on specific forms from the departments in question.DESCRIPTIVE DATA: From 1977 through 2014, ~110,000 patients are registered in the nationwide, clinical database. The completeness has gradually improved to more than 95%. DBCG has continuously prepared evidence-based guidelines on diagnosis and treatment of breast cancer and conducted quality control studies to ascertain the degree of adherence to the guidelines in the different departments.CONCLUSION: Utilizing data from the DBCG database, a long array of high-quality DBCG studies of various designs and scope, nationwide or in international collaboration, have contributed to the current updating of the guidelines, and have been an instrumental resource in the improvement of management and prognosis of breast cancer in Denmark. Thus, since the establishment of DBCG, the prognosis in breast cancer has continuously improved with a decrease in 5-year mortality from ~37% to 15%.

BACKGROUND:Over the past 40 years the Danish Breast Cancer Cooperative Group (DBCG) has made significant contributions to improve outcome and to make treatment of patients with early breast cancer more tolerable through nationwide and international trials evaluating loco-regional and systemic treatments. These trials have been instrumental to establish standards for the treatment of early breast cancer.METHODS:The DBCG 82 trials had a global impact by documenting that the significant gain in loco-regional recurrence from postmastectomy radiation added to systemic therapy was associated with a reduction in distant recurrence and mortality in high-risk pre- and postmenopausal patients. The DBCG trials comparing breast conserving surgery and radiotherapy with mastectomy and more recently the trial of internal mammary node irradiation also had a major impact of practice. The trials initiated by the DBCG 40 years ago on tamoxifen and cyclophosphamide based chemotherapy became instrumental for the development of adjuvant systemic therapy not only due to their positive results but by sharing these important data with other members of the Early Breast Cancer Trialist' Collaborative Group (EBCTCG). Trials from the DBCG have also been important for highlighting the relative importance of anthracyclines and taxanes in the adjuvant setting. Furthermore, DBCG has made a major contribution to the development of aromatase inhibitors and targeted adjuvant treatment for human epidermal growth factor receptor 2 positive breast cancers.RESULTS:The substantial impact of these treatment improvements is illustrated by a 46.7% 10-year overall survival of early breast cancer patients treated in 1978-1987 compared to 71.5% for patients treated 2008-2012.CONCLUSIONS:The trials conducted and implemented by the DBCG appear to have a major impact on the substantial survival improvements in breast cancer. BACKGROUND: Over the past 40 years the Danish Breast Cancer Cooperative Group (DBCG) has made significant contributions to improve outcome and to make treatment of patients with early breast cancer more tolerable through nationwide and international trials evaluating loco-regional and systemic treatments. These trials have been instrumental to establish standards for the treatment of early breast cancer.METHODS: The DBCG 82 trials had a global impact by documenting that the significant gain in loco-regional recurrence from postmastectomy radiation added to systemic therapy was associated with a reduction in distant recurrence and mortality in high-risk pre- and postmenopausal patients. The DBCG trials comparing breast conserving surgery and radiotherapy with mastectomy and more recently the trial of internal mammary node irradiation also had a major impact of practice. The trials initiated by the DBCG 40 years ago on tamoxifen and cyclophosphamide based chemotherapy became instrumental for the development of adjuvant systemic therapy not only due to their positive results but by sharing these important data with other members of the Early Breast Cancer Trialist' Collaborative Group (EBCTCG). Trials from the DBCG have also been important for highlighting the relative importance of anthracyclines and taxanes in the adjuvant setting. Furthermore, DBCG has made a major contribution to the development of aromatase inhibitors and targeted adjuvant treatment for human epidermal growth factor receptor 2 positive breast cancers.RESULTS: The substantial impact of these treatment improvements is illustrated by a 46.7% 10-year overall survival of early breast cancer patients treated in 1978-1987 compared to 71.5% for patients treated 2008-2012.CONCLUSIONS: The trials conducted and implemented by the DBCG appear to have a major impact on the substantial survival improvements in breast cancer.

BACKGROUND:Since 40 years, Danish Breast Cancer Cooperative Group (DBCG) has provided comprehensive guidelines for diagnosis and treatment of breast cancer. This population-based analysis aimed to describe the plurality of modifications introduced over the past 10 years in the national Danish guidelines for the management of early breast cancer. By use of the clinical DBCG database we analyze the effectiveness of the implementation of guideline revisions in Denmark.METHODS:From the DBCG guidelines we extracted modifications introduced in 2007-2016 and selected examples regarding surgery, radiotherapy (RT) and systemic treatment. We assessed introduction of modifications from release on the DBCG webpage to change in clinical practice using the DBCG clinical database.RESULTS:Over a 10-year period data from 48,772 patients newly diagnosed with malignant breast tumors were entered into DBCG's clinical database and 42,197 of these patients were diagnosed with an invasive carcinoma following breast conserving surgery (BCS) or mastectomy. More than twenty modifications were introduced in the guidelines. Implementations, based on prospectively collected data, varied widely; exemplified with around one quarter of the patients not treated according to a specific guideline within one year from the introduction, to an almost immediate full implantation.CONCLUSIONS:Modifications of the DBCG guidelines were generally well implemented, but the time to full implementation varied from less than one year up to around five years. Our data is registry based and does not allow a closer analysis of the causes for delay in implementation of guideline modifications. BACKGROUND: Since 40 years, Danish Breast Cancer Cooperative Group (DBCG) has provided comprehensive guidelines for diagnosis and treatment of breast cancer. This population-based analysis aimed to describe the plurality of modifications introduced over the past 10 years in the national Danish guidelines for the management of early breast cancer. By use of the clinical DBCG database we analyze the effectiveness of the implementation of guideline revisions in Denmark.METHODS: From the DBCG guidelines we extracted modifications introduced in 2007-2016 and selected examples regarding surgery, radiotherapy (RT) and systemic treatment. We assessed introduction of modifications from release on the DBCG webpage to change in clinical practice using the DBCG clinical database.RESULTS: Over a 10-year period data from 48,772 patients newly diagnosed with malignant breast tumors were entered into DBCG's clinical database and 42,197 of these patients were diagnosed with an invasive carcinoma following breast conserving surgery (BCS) or mastectomy. More than twenty modifications were introduced in the guidelines. Implementations, based on prospectively collected data, varied widely; exemplified with around one quarter of the patients not treated according to a specific guideline within one year from the introduction, to an almost immediate full implantation.CONCLUSIONS: Modifications of the DBCG guidelines were generally well implemented, but the time to full implementation varied from less than one year up to around five years. Our data is registry based and does not allow a closer analysis of the causes for delay in implementation of guideline modifications.

Background Adjuvant treatment in breast cancer patients especially with aromatase inhibitors (AIs) has adverse effects on bone metabolism resulting in an increased occurrence of fractures. In order to demonstrate this occurrence, long-term follow-up studies are necessary. From several national registries in Denmark, it is possible to link data from different sources and analyze this issue. Methods A study cohort of 68,842 breast cancer patients prospectively diagnosed and registered in the Danish Breast Cancer Cooperative Group's database during the period 1995-2012 formed the basis of the analysis. These data were matched with data on all types of fractures from the Danish National Patient Register and vital data from the Danish Civil Registration System. Results After data cleaning 66,502 patients were available for analysis and 16,360 of these had incurred 20,341 fractures with 13,182 patients having just one fracture. These fractures were distributed over 214 specific fracture sites. An extended multivariable Cox regression model revealed significant association between the occurrence of fractures and age, menopause, Charlson comorbidity index (CCI) and endocrine therapy such that late menopause and tamoxifen treatment were associated with a lower occurrence and AI treatment, age and CCI were associated with a higher occurrence of fractures. Conclusion Before advising adjuvant therapy with AIs fragile patients with chronic diseases should receive special attention in order to reduce the incidence of fractures in this vulnerable group of patients.

The capability to link health care information across various health care providers (institutions, clinics and professions) is increasingly recognized as an important source for clinical decision m...

The Danish Breast Cancer Group (DBCG) was established in 1977 by innovative and visionary clinicians and researchers diagnosing, treating and investigating breast cancer. The vision was to gather a...

Omission of chemotherapy may affect mortality in postmenopausal high-risk women despite appropriate adjuvant endocrine therapy for estrogen receptor (ER) positive breast cancer. The aim of this study was to determine how all-cause mortality rate in these patients compares to that of the general female population. Furthermore, to identify a subset without excess mortality using clinical and pathological characteristics.From the population-based database of the Danish Breast Cancer Cooperative Group we included 6529 postmenopausal patients with ER positive high-risk breast cancer who in 1996 through 2004 by nationwide guidelines were allocated to five years of tamoxifen, an aromatase inhibitor (AI) or both in sequence. Multivariate categorical and fractional polynomials (MFP) models were used to construct prognostic subsets by clinicopathologic characteristics.In a multivariate model excess mortality was inversely (p0.0001) associated with increasing age at surgery while recurrence-free survival (RFS) was not. Non-adherence to endocrine therapy was associated with excess mortality (p = 0.0008) while treatment with an AI was associated with a less pronounced mortality excess (p = 0.03). A prognostic standard mortality rate (SMR) index (PSI) was built using the regression coefficients obtained in the MFP model, and the same risk factors were used to construct a flowchart algorithm. Both allocated 75% to a group with increased all-cause mortality as compared to the general female population, but the SMR was significantly increased (SMR 1.38; 95% CI 1.16-1.65) in 462 patients who were allocated to low-risk group by the Flowchart algorithm and to a high-risk group by PSI.Only one quarter of postmenopausal ER positive breast cancer patients are free of excess mortality when omitting adjuvant chemotherapy. Patients should be informed about importance of adherence to adjuvant endocrine therapy and inclusion of an AI. A PSI may better guide recommendations regarding adjuvant chemotherapy.

TROMMELEN, J., A. M. HOLWERDA, I. W. K. KOUW, H. LANGER, S. L. HALSON, I. ROLLO, L. B. VERDIJK, and L. J. C. VAN LOON. Resistance Exercise Augments Postprandial Overnight Muscle Protein Synthesis Rates. Med. Sci. Sports Exerc., Vol. 48, No. 12, pp. 2517–2525, 2016. Introduction: We have previously shown that protein ingestion before sleep increases overnight muscle protein synthesis rates. Whether prior exercise further augments the muscle protein synthetic response to presleep protein ingestion remains to be established. Objective: This study aimed to assess whether resistance-type exercise performed in the evening increases the overnight muscle protein synthetic response to presleep protein ingestion. Methods: Twenty-four healthy young men were randomly assigned to ingest 30 g intrinsically L-[1-13C]-phenylalanine and L-[1-13C]-leucine-labeled casein protein before going to sleep with (PRO + EX, n = 12) or without (PRO, n = 12) prior resistance-type exercise performed in the evening. Continuous intravenous L-[ring- 2 H5]-phenylalanine, L-[1-13C]-leucine, and L-[ring- 2 H2]-tyrosine infusions were applied. Blood and muscle tissue samples were collected to assess whole-body protein balance, myofibrillar protein synthesis rates, and overnight incorporation of dietary protein-derived amino acids into de novo myofibrillar protein. Results: A total of 57% T 1% of the ingested protein-derived phenylalanine appeared in the circulation during overnight sleep. Overnight myofibrillar protein synthesis rates were 37% (0.055%Ihj1 T 0.002%Ihj1 vs. 0.040%Ihj1 T 0.003%Ihj1 , P G 0.001, based on L-[ring-2 H5]-phenylalanine) and 31% (0.073%Ihj1 T 0.004%Ihj1 vs. 0.055%Ihj1 T 0.006%Ihj1 , P = 0.024, based on L-[1-13C]-leucine) higher in PRO + EX compared with PRO. Substantially more of the dietary protein-derived amino acids were incorporated into de novo myofibrillar protein during overnight sleep in PRO + EX compared with PRO (0.026 T 0.003 vs. 0.015 T 0.003 molar percent excess, P = 0.012). Conclusions: Resistance-type exercise performed in the evening augments the overnight muscle protein synthetic response to presleep protein ingestion and allows more of the ingested protein-derived amino acids to be used for de novo myofibrillar protein synthesis during overnight sleep. Key Words: SLEEP, RECOVERY, EXERCISE, MUSCLE, STABLE ISOTOPES, CASEIN

Background Breast cancer mortality has declined from 1995 through 2012 which may be attributed to earlier diagnosis, changes in lifestyle risk factors, and improved treatments. To a large extent the relative contribution of these modalities are unknown. Mammography screening was introduced late in Denmark; in 1995 around 20% of the Danish female population aged 50-69 was covered by population-based screening, and this was in 2008 extended to the entire population. Breast conserving surgery gradually replaced mastectomy, and sentinel node biopsy was introduced. In the same period adjuvant treatment was extended considerable. Methods A population-based study of 68 842 breast cancer patients registered in the clinical database of the Danish Breast Cancer Cooperative Group in 1995-2012. Comprehensive data on prognostic factors, comorbidity and treatment together with complete follow-up for survival were used to evaluate improvements in mortality and standardized mortality rate in successive time periods. Results The results from this study demonstrated a significant improvement in prognosis in successive time periods covering 1995-2012. Apart from patients with a high Charlson Comorbidity Index (CCI) improvements were seen in all subgroups of patients. Prognostic factors were more favorable in the latest time period accordingly to the introduction of nationwide screening. In the study period adjuvant treatment was extended considerable. Conclusion The impact of screening was by nature of limited magnitude. The modified treatment strategies implemented by the use of nationwide guidelines seemed to have a major impact on the substantial survival improvements.

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.

Skeletal muscle atrophy is a primary clinical symptom associated with many diseases such as cachexia, sarcopenia, diabetes, neurodegenerative disorders and myopathies. This article is protected by copyright. All rights reserved

The SBG 2000-1 trial is a randomised study that investigates if dose-tailored adjuvant FEC therapy based on the individual's leukocyte nadir value can improve outcome. The study has included 1535 women with medium and high-risk breast cancer.After a first standard dosed FEC course (5-fluorouracil 600 mg/m(2), epirubicin 60 mg/mg(2) and cyclophosphamide 600 mg/m(2)), patients who did not reach leukopenia grade III or IV were randomised to standard doses (group standard) or doses tailored to achieve grade III leukopenia (group tailored) at courses 2-7. Patients who achieved leukopenia grade III or more after the first course were not randomised but continued on standard doses (group registered).Both planned and actually delivered number of courses (seven) were the same in all three arms. The relative dose intensity was increased by a factor of 1.31 (E 1.22, C 1.43) for patients in the tailored arm compared to the expected on standard dose. Ninety percent of the patients in the tailored arm achieved leukopenia grade III-IV compared with 29% among patients randomised to standard dosed therapy. Dose tailoring was associated with acceptable acute non-haematological toxicity with more total alopecia, nausea, vomiting and fatigue.Dose tailoring according to leukopenia was feasible. It led to an increased dose intensity and was associated with acceptable excess of acute non-haematological toxicity.

Background: Plasma levels of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) have been reported as predictors of poor prognosis. Indeed, in a previous study of 519 primary breast cancer patients we reported that high levels of TIMP-1 were associated with a poor prognosis (Würtz et al, 2008). In our previous study we quantified total levels of TIMP-1 in plasma; however, TIMP-1 is present in plasma in a non-complexed form and bound to various proteins. Thus, studying the different fractions might refine prognostic stratification and provide further insight into the role of TIMP-1 in tumor biology. Matrix Metalloproteinase-9 (MMP-9) is an important TIMP-1 binding partner and MMP-9 has previously been suggested as a breast cancer biomarker (Li et al, 2004; Somiari et al, 2006). Aim: The aim of the study was to analyze the concentration of MMP-9/TIMP-1 complexes in plasma from our previously studied primary breast cancer patients and evaluate whether these levels are associated with disease outcome. Materials and methods: Plasma concentrations of MMP-9/TIMP-1 complexes were measured using the human MMP-9/TIMP-1 Complex DuoSet® ELISA Development System (R&D Systems, Inc.) The ELISA was thoroughly validated for measurements of MMP-9/TIMP-1 complexes in EDTA plasma. Samples included preoperatively obtained EDTA plasma from consecutively enrolled patients with primary breast cancer. Of the previously studied 519 patients, 483 had plasma samples available for analysis and follow-up data registered by the Danish Breast Cancer Cooperative Group and were included in the present study. The median follow-up time was 5.1 years. The relationship between MMP-9/TIMP-1 complexes and classical prognostic parameters was analyzed and the association with recurrence-free survival (RFS; includes breast cancer relapse, contralateral breast cancer, other malignant disease, and death without a previous relapse) was studied. Results: The ELISA was validated with acceptable results. The median TIMP-1 concentration was 2.06 ng/mL. For analysis, patients were grouped in quartiles of increasing MMP-9/TIMP-1 plasma concentrations. MMP-9/TIMP-1 complex levels were associated with menopausal status and with hormone receptor status; no significant associations with other clinico-pathological parameters (tumor size, nodal status, malignancy grade, age) were found. No statistically significant difference in survival was observed among TIMP-1 high and low groups (quartiles, log-rank analysis p=0.96). In a Cox multivariable analysis (including tumor size, nodal status, hormone receptor status, malignancy grade, menopausal status, age), only age (> 70 years) and hormone receptor status contributed significantly to the model for RFS (P Conclusions: In this group of primary breast cancer patients we did notfind any association between MMP-9/TIMP-1 complex levels in plasma and RFS. Total TIMP-1 levels have previously been shown to correlate with prognosis in this patient cohort. Accordingly, our current results point to other TIMP-1 fractions, i.e. the fraction of free TIMP-1 or TIMP-1 in complex with other plasma proteins, as potential indicators of poor prognosis. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-07-04.

Breast cancer is a major cause of morbidity and mortality in postmenopausal women worldwide. Reducing the risk of distant disease recurrence is a primary goal of adjuvant endocrine therapy. As we await data from ongoing Phase III comparison trials, an emerging body of evidence demonstrates important differences between third-generation aromatase inhibitors, particularly with respect to potency and prevention of early distant metastases. Furthermore, a growing body of evidence demonstrates anticancer benefits of bisphosphonates in adjuvant breast cancer and other settings. This article outlines the proceedings from an Expert Panel meeting of regionally diverse breast cancer specialists regarding the appropriate use of aromatase inhibitors in postmenopausal hormone-responsive early breast cancer and bisphosphonates as anticancer therapy in adjuvant breast cancer.

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 purpose of this study was to evaluate the association between response at recurrence to letrozole versus tamoxifen and the expression of estrogen regulated proteins individually and combined in an "ER activity profile" in primary tumor tissue. Our hypothesis is that letrozole may be more effective than tamoxifen for treatment of tumors with high intratumoral estrogen content, whereas tamoxifen may be more efficient for treatment of tumors with high levels of the estrogen receptor (ER) and low intratumoral estrogen content.For this study, we produced tissue microarrays from formalin fixed paraffin embedded primary tumor material from a subgroup of patients (9.4%), who have participated in the international, randomized, phase III clinical trial PO25 comparing letrozole with tamoxifen in 907 patients with advanced breast cancer. The expression levels of ER, the progesterone receptor (PR), the anti-apoptotic protein Bcl-2 and the Insulin like Growth Factor Receptor I (IGF-IR) were determined by semi-quantitative immunohistochemistry.Response to letrozole and tamoxifen treatment, measured as time to progression (TTP), was independent of primary tumor expression level of ER, Bcl-2 and IGF-IR. However, high expression of PR as well as high expression of three different ER activity profiles; ER/PR/Bcl-2, ER/PR/IGF-IR and ER/PR/Bcl-2/IGF-IR identified letrozole treated patients with significantly longer TTP. The ER activity profile including ER, PR, Bcl-2 and IGF-IR showed a trend towards being a selection criterion for letrozole versus tamoxifen therapy.This small sub-study supports our hypothesis that letrozole is superior to tamoxifen primarily in patients expressing high levels of estrogen regulated proteins in the primary tumor tissue. Furthermore, it seems that the "ER activity profile" with high PR, IGF-IR and Bcl-2 is a promising selection criterion, regarding prediction of response to letrozole versus tamoxifen.

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: 2008 BACKGROUND: Previous analyses of TOP2A and HER2 in the Danish Breast Cancer Coopererative Group (DBCG) trial 89D suggested that TOP2A amplifications and possible also deletions are predictive markers for the effect of adjuvant epirubicin in patients with primary breast cancer. We present an updated and extended statistical analysis, requested for IVD-labeling of TOP2A testing. MATERIAL AND METHODS: In the DBCG trial 89D 980 Danish patients were randomly assigned to nine cycles of intravenous CMF (cyclophosphamide, methotrexate, and fluorouracil) or CEF (cyclophosphamide, epirubicin, and fluorouracil). Archival tumor tissue was collected retrospectively from 806 of these patients in a prospectively designed, biological sub-study, and was successfully analyzed for TOP2A aberrations and HER2 status in 773 samples (96%). Recurrence-free survival (RFS) was the primary endpoint. RESULTS: TOP2A aberrations (amplifications and deletions) were significantly associated with shorter RFS (p

BACKGROUND: In patients with COPD and isolated night time hypoxemia, oxygen administration has not shown any effects on life expectancy and the development of pulmonal arterial hypertension. The aim of the present pilot study was to investigate the influence of nocturnal oxygen therapy on the quality of life in daytime normoxemic COPD patients with nocturnal oxygen desaturations. PATIENTS AND METHODS: 19 patients with COPD, in a stable phase of the disease without need for oxygen supplementation under rest (PaO 2 62.7 ± 4.9 mm Hg) and nocturnal hypoxemia (t 90 = 55.5 ± 33.4 % of registration time, mean SaO 2 89.8 ± 1.9 %, minimal SaO 2 81.1 ± 4.8 %) were randomly assigned to either oxygen or placebo treatment, both generated by identical concentrator devices. Each treatment period lasted 6 weeks, after six weeks a cross-over was performed by a technician. Quality of life was assessed before and at the end of each treatment period by the SF-36, Nottingham Health Profile and Saint George’s Respiratory Questionnaire. RESULTS: Significant differences for the comparison of placebo and verum were only seen for the dimension sleep (NHP), all other dimensions showed no differences between placebo and oxygen. However, both placebo and oxygen improved the majority of the quality of life items significantly. CONCLUSIONS: The prescription of supplemental oxygen in COPD patients with isolated nocturnal hypoxemia in the present pilot study is not able to improve the quality of life within 6 weeks after initiation of therapy. It cannot, therefore, be generally recommended, but may be indicated in patients with a documented improvement of sleep quality.

Udgivelsesdato: 2008-null DBCG (Danish Breast Cancer Cooperative Group) constitutes a multidisciplinary organization established in 1975 by the Danish Surgical Society. The purpose involves first and foremost a nation-wide standardization of breast cancer treatment based on novel therapeutic principles, collaboration between experts handling diagnostic work-up, surgery, radiotherapy, medical oncology, and basic research, and, further, complete registration of relevant clinical data in a national data base attached to DBCG. Data are processed by the Secretariat personnel composed of statisticians, data managers, and data secretaries making current analyses of outcome results feasible. DBCG is run by the Executive Committee consisting of expert members appointed by their respective society. From 1978 the DBCG project gained widely accession from participating units, and since then nearly all newly diagnosed breast cancer incident cases are reported and registered in the national data base. Today, the data base includes approximately 80 000 incidents of primary breast cancer. Annually, the Secretariat receives roughly 1.5 million parameters to be entered into the data base. Over time DBCG has generated seven treatment programmes including in situ lesions and primary invasive breast cancer. Probands are subdivided into risk groups based on a given risk pattern and allocated to various treatment programmes accordingly. The scientific initiatives are conducted in the form of register- and cohort analysis or randomized trials in national or international protocolized settings. Yearly, about 4 000 new incident cases of primary invasive breast cancer and about 200 in situ lesions enter the national programmes. Further, about 600 women with hereditary disposition of breast cancer are registered and evaluated on a risk scale. The main achievements resulted in a reduction of relative risk of death amounting up to 20% and increased 5-year overall survival ascending from 60% to roughly 80%. This article is partly based on a Danish paper to be published in the Centenary Jubilee book of the Danish Surgical Society, 2008.

The main objective of the present study aims at comparing the long-term efficacy of breast conserving surgery (BCS) vs. mastectomy (M) based on a randomized design. The Danish Breast Cancer Cooperative Group (DBCG) conducted the trial (DBCG-82TM) from January 1983 to March 1989 recruiting 1154 patients with invasive breast carcinoma. Follow-up time ended 1(st) May 2006 with a median follow-up time of 19.6 years (time span 17.1-23.3 years). Eligibility criteria included a one-sided, unifocal, primary operable breast carcinoma, patient age below 70 years, probability of satisfactory cosmetic outcome with BCS, and no evidence of disseminated disease. The patients accrued were grouped into three subsets: correctly randomized, suspicion of randomization error, and declining randomization. The main analyses focus on the subgroup of 793 correctly randomized patients representing 70% of the complete series. 10-year recurrence free survival (RFS) and 20-year overall survival (OS) based on intent to treat did not reveal significant differences in outcome between breast conserving surgery vs. mastectomy, p=0.95 and p=0.10, respectively. Including the complete series comprising 1133 eligible patients based on treatment in fact given similarly no significant difference between surgical options could be traced in outcome of 10-year RFS and 20-year OS, p=0.94 and p=0.24, respectively. The pattern of recurrences as a first event in breast conservation vs. mastectomy did not differ significantly irrespective of site, p=0.27. Looking into the type of local relapse, viz., new primaries vs. true recurrences, it appeared that new primaries were significantly associated to BCS, while true recurrences dominated among M treated patients (p

A significant reduction in the risk of recurrence and death was achieved three decades ago with adjuvant chemotherapy in patients with operable breast. The major pivotal trials used oral cyclophosphamide (C) days 1-14 with intravenous methotrexate (M) and fluorouracil (F) on days 1 and 8, repeated every 28 days. The classical CMF has later been modified as concerns dose and schedule, without formal comparisons in randomised trials between the classical CMF and the modifications.Classical CMF was used in the first adjuvant chemotherapy trial performed by the Danish Breast Cancer Cooperative Group (DBCG), and two succeeding randomised trials in premenopausal patients with node positive breast cancer used three-weekly or four-weekly intravenous CMF in one of the treatment arms.Between November 1977 and January 2001 these trials included 2 213 patients who in addition to surgery and radiotherapy received CMF. Ten-year disease-free survival (DFS) rates were 48% following classical CMF, 45% following four-weekly and 47% following three-weekly CMF. Major differences in patient characteristics were observed across these three cohorts, and a multivariate analysis was performed adjusting for the known prognostic factors. In the adjusted analysis a 30% increase in the risk of recurrence was observed for two the intravenous regimens as compared to classical CMF. As concerns survival a significant 40% increase in the risk of death was observed with the four-weekly regimen, while a similar risk of death was observed with the three-weekly intravenous. Classical CMF was associated with a higher risk of amenorrhoea, and this may at least in part explain an observed interaction between age and efficacy.This cross trial comparison suggests a detrimental effect in premenopausal patients with node positive breast cancer when shifting from classical CMF to intravenous regimens with lower dose-intensity. Caution is required in the interpretation of these results due to the non-experimental study design.

Udgivelsesdato: 2008-null Introduction. Since 30 years, DBCG (Danish Breast Cancer Cooperative Group) has maintained a clinical database allowing the conduct of quality control studies, of randomised trials, examination of the epidemiology of breast cancer and of prognostic and predictive factors. Material and methods. The original database included patients with invasive breast cancer, but has later been expanded to patients with in situ breast cancer and hereditary breast and ovarian cancer families. Results. The multidisciplinary cooperative group has provided successive treatment guidelines and 70% of the 77284 registered patients have been enrolled and received treatment according to these guidelines. The standard treatments and the randomised trials included in the DBCG programmes are all briefly described. Among high-risk patients 48% have participated in randomised trials, and the results of these trials have largely been implemented in the next generation of treatment guidelines. Records within the clinical database of archival tumour tissue have established a basis for translational research and epidemiologic research has been enabled through linkage to other healthcare registries. Discussion. The joint conception of the multidisciplinary breast cancer group and a clinical database has provided improvements in the management of breast cancer patients and has enabled recruitment of patients onto randomised trials.

Estrogen receptor (ER) status is considered as an important prognostic factor as well as a predictive factor for endocrine responsiveness in breast cancer. We analyzed the distribution of ER status across age and estimated variations in the prognostic impact of ER status related to patients' age and time since diagnosis. Overall, 26,944 patients with primary breast cancer diagnosed from 1989 to 2004 were included. The proportion of ER positive tumors increased over age from 51 to 82%. In multivariate analysis of overall survival, ER positive status was found to be a significantly positive prognostic factor over all age groups. This effect was limited to the first 5 years after diagnosis, RR: 2.08 (95% CI: 1.95-2.22, p < 0.0001). Overall survival during the following 5 years was slightly superior for women with ER negative tumors, RR of death: 0.89 (95% CI: 0.79-1.00, p = 0.049). Results were unchanged in patients who did not receive adjuvant systemic therapy (n = 6,272). Thus, positive ER status does not confer a negative impact on survival in young women as has been previously reported. The inferior prognosis for ER negative patients during the first 5 years after diagnosis changes into a slightly superior residual prognosis compared to ER positive patients independent of use of adjuvant systemic therapy. This may have an impact on future designing of guidelines for adjuvant endocrine therapy beyond 5 years.

Flow cytometric DNA analysis was performed on fine-needle aspirates from frozen tumour biopsies from 421 node-negative, non-adjuvantly-treated breast-cancer patients with a median observation time of 6.75 years. Among premenopausal patients (n = 175), those having at least one DNA "hypoploid" subpopulation defined as DNA index (DI) < 0.96 or 1.44 < or = 1.92 (n = 81) were characterized by early recurrences (log-rank p = 0.05), Wilcoxon p = 0.007), poor overall survival (OS) (p < 0.001) and poor survival after recurrence (p < 0.001). In the postmenopausal group (n = 246), there were no significant difference among 7 different DI classes regarding either recurrence-free survival (RFS) or OS. S-phase fraction (SPF), divided into quartiles, predicted OS in premenopausal patients only (p = 0.02). Conventional multivariate Cox analysis of OS in the premenopausal group revealed hypoploidy to be the only independent prognostic factor involving a relative risk (RR) of 22.8. Age < or = 40 years was of marginal significance, whereas SPF, histological grade (WHO), oestrogen and progesterone receptor (PgR) content, tumour size and number of lymph nodes removed were excluded from the model. Application of the conventional Cox model to the premenopausal group regarding RFS was found inappropriate due to lack of proportionality of the hazards of hypoploidy due to lack of proportionately of the hazards of hypoploidy, SPF and histological grade. However, introduction of time-dependent co-variates using 2 years as cut-off level showed hypoploidy with a RR of 3.52 and age < or = 40 years with a RR of 3.28 to be independent prognostic factors. In the postmenopausal group, the conventional Cox model identified the number of lymph nodes removed to be the only independent prognostic factor regarding RFS as well as OS, whereas SPF < 9% (lowest quartile) was of marginal significance in RFS analysis. Hypoploidy was correlated to high SPF, low PgR content and low differentiation, indicating that hypoploid tumours proliferate rapidly and hormone-independently. These patients may therefore benefit from adjuvant chemotherapy administered while tumour burden and risk of drug resistance are still low.

Approximately 25 % of all patients suffering from obstructive sleep apnea syndrome (OSAS) discontinue CPAP-therapy in long-term follow-up. This study was conducted to investigate if there are any predictors signaling low compliance prior to initiation of CPAP-therapy. We used an open label longitudinal cohort study at an University hospital in-patient Sleep laboratory setting. In 85 consecutive patients with a diagnosis of OSAS confirmed by polysomnography a CPAP-therapy was initiated. Prior to CPAP-titration the subjects were interviewed using standardized, validated questionnaires (Nottingham Health Profile, von Zerssen's Depression Scale, State Trait Anxiety Inventory, IPC-Scale). On follow up (mean 16 +/- 8 month) 66 patients were still using CPAP regularly, 19 individuals had discontinued the therapy. Data of both groups were compared. There were no significant differences in polysomnographic parameters before CPAP except apnea-hypopnea-index (users: 30.72 +/- 20.68, rejecters: 18.43 +/- 10.43) and mean oxygen saturation (users: 91.65 +/- 3.32, rejecters 93.63 +/- 1.86). Depression and anxiety levels were normal in both groups. The subjects who discontinued CPAP had a significantly less external control belief. Internal control belief was normal in all patients. It is suggested that individuals who discontinued CPAP could not be convinced of the necessity of CPAP by physicians or nurses due to their reduced external control belief. Identifying patients with diminished external control belief prior to prescription of a device might be useful. In selected subgroups, different methods of motivation to maintain long-term acceptance for CPAP-therapy seems to be necessary.

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

This study examined whether psychological distress in newly diagnosed breast cancer patients was associated with their survival. We analyzed data from 1,588 breast cancer patients who filled in the EORTC QLQ-C30 questionnaire and the Hospital Anxiety and Depression Scale (HADS) 2 months after their primary operation. The median follow-up time was 12.9 years. Psychological distress (EORTC QLQ-C30 emotional function; HADS anxiety; HADS depression) and EORTC fatigue, physical function, and overall ratings were used to predict recurrence-free and overall survival, controlling for the known clinical and histopathological prognostic factors (biological model) using Cox multivariate regression analysis. Low levels of psychological distress (good EORTC emotional function) and low fatigue independently predicted longer recurrence-free and overall survival, controlling for biological factors. Lack of anxiety (HADS) also predicted longer recurrence-free survival. When added in combination to the biological model, fatigue remained a significant predictor of recurrence-free survival (P = 0.0004; risk ratio 1.32 (1.13-1.54)) and emotional function remained a significant predictor of overall survival (P = 0.0074; risk ratio 0.81 (0.70-0.95)). Low psychological distress and a low level of fatigue may cause a greater cancer resistance or may reflect underlying mental and physical robustness.

Purpose: Only about 50% of metastatic breast cancer patients benefit from cytotoxic chemotherapy. Today, no validated markers exist for prediction of chemotherapy sensitivity/resistance in this patient group. Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to protect against apoptosis, and the purpose of the present study was to test the hypothesis that tumors expressing high levels of TIMP-1 are protected against apoptosis-inducing agents and thus less sensitive to apoptosis-inducing chemotherapeutic drugs. Experimental Design: We investigated the association between primary tumor expression levels of TIMP-1 protein and objective response to first-line chemotherapy in 173 patients with metastatic breast cancer. Results: When analyzed as a continuous log-transformed variable, increasing TIMP-1 levels were significantly associated with lack of response to cyclophosphamide/methotrexate/5-fluorouracil and anthracycline-based chemotherapy (P = 0.01; odds ratio, 2.0; 95% confidence interval, 1.1-3.3). In a multivariate model, including lymph node status, steroid hormone receptor status, menopausal status, dominant metastases site, type of chemotherapy, and disease-free interval, TIMP-1 was significantly associated with resistance to treatment (P = 0.03; odds ratio, 1.7; 95% confidence interval, 1.1-3.3). Conclusions: In the present exploratory study, we showed that elevated tumor tissue TIMP-1 levels were significantly associated with a poor response to chemotherapy. By using TIMP-1, we identified a group of patients with metastatic breast cancer, which hardly respond to the most frequently used chemotherapy regimes (i.e., cyclophosphamide/methotrexate/5-fluorouracil and anthracyclines).

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.

Ovarian ablation is an effective adjuvant therapy for primary breast cancer but little is known about its quality of life impact relative to the more widely used adjuvant chemotherapy. This randomized study compared quality of life outcomes of adjuvant ovarian ablation versus cyclophosphamide, methotrexate, fluoracil (CMF) chemotherapy.The Danish Breast Cancer Cooperative Group (DBCG) trial 89-b randomized premenopausal patients with receptor-positive, primary breast cancer between nine cycles of CMF chemotherapy given every 3 weeks and ovarian ablation by oophorectomy. In total, 317 randomized patients were invited to take part in a longitudinal quality of life study with assessments at 1, 3, 5, 9, 15, and 24 months after randomization. The questionnaire included the EORTC QLQ-C30, the Hospital Anxiety and Depression Scale, and additional items assessing potential symptoms not included in the standard instruments.After 2 years, 260 women were alive and recurrence-free, and 196 of these (75%) had completed all six questionnaires. Overall, patients in the chemotherapy group had more symptomatology at the first three assessments (i.e., during the 6 months treatment period), except for hot flushes/sweats. There were few differences between groups at later assessments. In chemotherapy patients, the likelihood of preserving ovarian function decreased steeply with increasing age. CMF chemotherapy and ovarian ablation have similar impact on recurrence and survival.Chemotherapy had more negative impact on health-related quality of life but preserved ovarian function in some younger patients.

Purpose The aim of the study was to evaluate the predictive value of HER2 and topoisomerase IIα gene (TOP2A) for the efficacy of epirubicin in the adjuvant setting of breast cancer patients. Patients and Methods In the Danish Breast Cancer Cooperative Group trial 89D, 980 pre- and postmenopausal primary patients were randomly allocated to either CMF (cyclophosphamide, methotrexate, and fluorouracil; n = 500) or CEF (cyclophosphamide, epirubicin, and fluorouracil; n = 480) times 9, between January 1990 and November 1999. Tumor tissue was retrospectively identified from 805 patients and was analyzed for HER2-positivity and for TOP2A-amplifications and deletions. Results HER2-positivity was found in 33% of the 805 investigated tumors and was not a predictive marker for epirubicin sensitivity. TOP2A changes were identified in 23% of the 773 investigated tumors: 12% had TOP2A amplifications and 11% had TOP2A deletions. We found that patients with TOP2A amplification had an increased recurrence-free (RFS; hazard ratio [HR], 0.43; 95% CI, 0.24 to 0.78) and overall survival (OS; HR, 0.57; 95% CI, 0.29 to 1.13), respectively if treated with CEF compared with CMF, and that patients with TOP2A deletions had an almost identical hazard ratio (RFS: HR, 0.63; 95% CI, 0.36 to 1.11; OS: HR, 0.56; 95% CI, 0.30 to 1.04). This is in contrast to patients with a normal TOP2A genotype for whom similar outcome was observed in both treatment arms (RFS: HR, 0.90; 95% CI, 0.70 to 1.17; OS: HR, 0.88; 95% CI, 0.66 to 1.17). Conclusion TOP2A amplification—and possibly deletion—seems to be predictive markers for the effect of adjuvant epirubicin containing therapy in primary breast cancer, but a final conclusion has to await a confirmative study or a meta-analysis.

Endocrine therapy, predominantly using the antioestrogen tamoxifen, has long been a key treatment strategy for oestrogen receptor-positive breast cancer. An alternative approach is to treat patients with aromatase inhibitors, which suppress oestrogen biosynthesis. Letrozole, and other third-generation aromatase inhibitors, are highly specific and potent inhibitors of oestrogen production, which markedly reduce circulating oestrogen levels and whole-body aromatisation of androgen precursors after menopause. In postmenopausal women with hormone receptor-positive or receptor-unknown breast cancer, letrozole has been shown to be superior to megestrol acetate and aminoglutethimide in second-line treatment for advanced breast cancer. Letrozole was also superior to tamoxifen in first-line treatment for advanced breast cancer, as well as in systemic preoperative (neoadjuvant) treatment of locally advanced breast cancer. A recent adjuvant trial demonstrated significant superiority of letrozole over tamoxifen in disease-free survival, and another trial demonstrated that treatment for early breast cancer with letrozole, following 5 years of adjuvant tamoxifen (extended adjuvant therapy), significantly improved disease-free survival compared with placebo, irrespective of nodal status. Ongoing trials will determine whether the optimal use of letrozole in the adjuvant therapy of early breast cancer is as a replacement for tamoxifen, or sequenced additionally before or after tamoxifen.

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.

Discovery-driven translational research in breast cancer is moving steadily from the study of cell lines to the analysis of clinically relevant samples that, together with the ever increasing number of novel and powerful technologies available within genomics, proteomics and functional genomics, promise to have a major impact on the way breast cancer will be diagnosed, treated and monitored in the future. Here we present a brief report on long-term ongoing strategies at the Danish Centre for Translational Breast Cancer Research to search for markers for early detection and targets for therapeutic intervention, to identify signalling pathways affected in individual tumours, as well as to integrate multiplatform ‘omic’ data sets collected from tissue samples obtained from individual patients. The ultimate goal of this initiative is to coalesce knowledge-based complementary procedures into a systems biology approach to fight breast cancer.

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.

Purpose To determine whether the addition of intravenous (IV) vinorelbine to epirubicin increased the progression-free survival in first-line treatment of metastatic breast cancer. Patients and Methods A total of 387 patients were randomly assigned to receive IV epirubicin 90 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8, or epirubicin 90 mg/m2 IV on day 1. Both regimens were given every 3 weeks for a maximum of 1 year but discontinued prematurely in the event of progressive disease or severe toxicity. In addition, epirubicin was discontinued at a cumulative dose of 1,000 mg/m2 (950 mg/m2 from June 1999). Prior anthracycline-based adjuvant chemotherapy and prior chemotherapy for metastatic breast cancer was not allowed. Reported results were all based on intent-to-treat analyses. Results Overall response rates to vinorelbine and epirubicin, and epirubicin alone, were 50% and 42%, respectively (P = .15). The complete response rate was significantly superior in the combination arm (17% v 10%; P = .048) as was median duration of progression-free survival (10.1 months v 8.2 months; P = .019). Median survival was similar in the two arms (19.1 months v 18.0 months; P = .50). Leukopenia related complications, stomatitis, and peripheral neuropathy were more common in the combination arm. The incidences of cardiotoxicity and constipation were similar in both arms. Conclusion Addition of vinorelbine to epirubicin conferred a significant advantage in terms of complete response rate and progression-free survival, but not in terms of survival.

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.

Die ambulante Versorgung von Patienten mit einer koronaren Herzkrankheit (KHK) sollte neben der Diagnostik vor allem die medikamentose Therapie und Pravention gewahrleisten. Ziel dieser Studie war die Erhebung der Versorgungsqualitat im medikamentosen und praventiven Bereich bei Patienten mit einer KHK. Die prospektive Untersuchung wurde von Marz 1999 bis Februar 2002 am Universitatsklinikum Bergmannsheil, Bochum, durchgefuhrt. Eingeschlossen wurden 300 konsekutive Patienten mit der Einweisungsdiagnose KHK ohne Herzinfarkt und Koronarangiographie in der Vergangenheit. Diagnostik und Therapie richteten sich nach den aktuellen Leitlinien. 248 Patienten (82,7%), 116 davon mit einer angiographisch nachgewiesenen KHK, wurden nach 1 Jahr erneut untersucht. Bei der Abschlussuntersuchung erhielten nur noch 70,9% der Patienten mit einer KHK einen β-Blocker und 83,6% einen Thrombozytenaggregationshemmer. Der Bodymass-Index, der Anteil ubergewichtiger Patienten und der HbA1c bei Diabetikern anderten sich im Verlauf der Untersuchung nicht. Nach 1 Jahr hatten 48,0% der Patienten einen systolischen Blutdruck > 139 mmHg, 22,6% einen diastolischen Wert > 89 mmHg. Bei der Nachkontrolle lag der LDL-Wert in 57,0% der Falle oberhalb der empfohlenen Zielbereiche. Der hohe Anteil inadaquat therapierter Patienten war sowohl in der Gruppe der Patienten mit wie ohne KHK nachweisbar. Die medikamentose Therapie und die primar- wie sekundarpraventiven Masnahmen der beobachteten Patienten waren mangelhaft. Es zeigten sich deutliche Defizite in der Versorgungsqualitat dieser Patienten. Offensichtlich mangelt es nicht an der Verfugbarkeit evaluierter, effektiver und effizienter Masnahmen, sondern an deren Umsetzung in die Praxis. Arztlicherseits sollten Bemuhungen zur Implementierung der vorhandenen evidenzbasierten Leitlinien verstarkt werden.

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.