202 research outputs found
Long-term effectiveness of adjuvant Goserelin in premenopausal women with early breast cancer
No full textBACKGROUND: Systematic reviews have found that luteinizing hormone-releasing hormone (LHRH) agonists are effective in treating premenopausal women with early breast cancer. METHODS: We conducted long-term follow-up (median 12 years) of 2706 women in the Zoladex In Premenopausal Patients (ZIPP), which evaluated the LHRH agonist goserelin (3.6 mg injection every 4 weeks) and tamoxifen (20 or 40 mg daily), given for 2 years. Women were randomly assigned to receive each therapy alone, both, or neither, after primary therapy (surgery with or without radiotherapy/chemotherapy). Hazard ratios and absolute risk differences were used to assess the effect of goserelin treatment on event-free survival (breast cancer recurrence, new tumor or death), overall survival, risk of recurrence of breast cancer, and risk of dying from breast cancer, in the presence or absence of tamoxifen. RESULTS: Fifteen years after the initiation of treatment, for every 100 women not given tamoxifen, there were 13.9 (95% confidence interval [CI] = 17.5 to 19.4) fewer events among those who were treated with goserelin compared with those who were not treated with goserelin. However, among women who did take tamoxifen, there were 2.8 fewer events (95% CI = 7.7 fewer to 2.0 more) per 100 women treated with goserelin compared with those not treated with goserelin. The risk of dying from breast cancer was also reduced at 15 years: For every 100 women given goserelin, the number of breast cancer deaths was lower by 2.6 (95% CI = 6.6 fewer to 2.1 more) and 8.5 (95% CI = 2.2 to 13.7) in those who did and did not take tamoxifen, respectively, although in the former group the difference was not statistically significant. CONCLUSIONS: Two years of goserelin treatment was as effective as 2 years of tamoxifen treatment 15 years after starting therapy. In women who did not take tamoxifen, there was a large benefit of goserelin treatment on survival and recurrence, and in women who did take tamoxifen, there was a marginal potential benefit on these outcomes when goserelin was added
The occurrence of invasive cancers following a diagnosis of breast carcinoma in situ.
No full textApproximately 1 in every 600 women attending breast-screening programmes in the United Kingdom is diagnosed with breast carcinoma in situ (BCIS). However, there is little information on the occurrence of subsequent cancers (other than second breast cancers) in these women. We investigated the occurrence of invasive cancers in 12,836 women diagnosed with BCIS in southeast England between 1971 and 2003, using data from the Thames Cancer Registry. A greater than expected number of subsequent cancers was found for two sites: breast (standardised incidence ratio (SIR) 1.96; 95% confidence interval (CI) 1.79-2.14) and corpus uteri (SIR 1.42; 95% CI 1.11-1.78). For subsequent ipsilateral breast cancer in those treated with breast conservation, the excess was independent of the time since diagnosis of BCIS, whereas for subsequent contralateral breast cancer, there was a steady decline in excess over time. For subsequent uterine cancer, the excess became statistically significant only at >5 years after BCIS diagnosis, consistent with a treatment effect. This was further supported by Cox regression analysis: the risk of subsequent uterine cancer was significantly increased in women receiving hormonal therapy compared with those not receiving it, with a hazard ratio of 2.97 (95% CI 1.84-4.80)
The conquest of middle-earth: Combining top-down and bottom-up nanofabrication for constructing nanoparticle based devices
No full textThe development of top-down nanofabrication techniques has opened many possibilities for the design and realization of complex devices based on single molecule phenomena such as e.g. single molecule electronic devices. These impressive achievements have been complemented by the fundamental understanding of self-assembly phenomena, leading to bottom-up strategies to obtain hybrid nanomaterials that can be used as building blocks for more complex structures. In this feature article we highlight some relevant published work as well as present new experimental results, illustrating the versatility of self-assembly methods combined with top-down fabrication techniques for solving relevant challenges in modern nanotechnology. We present recent developments on the use of hierarchical self-assembly methods to bridge the gap between sub-nanometer and micrometer length scales. By the use of non-covalent self-assembly methods, we show that we are able to control the positioning of nanoparticles on surfaces, and to address the deterministic assembly of nano-devices with potential applications in plasmonic sensing and single-molecule electronics experiments. This journal i
Estrogen Receptor-alpha Phosphorylation at Serine 305, Nuclear p21-Activated Kinase 1 Expression, and Response to Tamoxifen in Postmenopausal Breast Cancer
No full textPurpose: In vitro, p21-activated kinase 1 (Pak1) phosphorylates the serine 305 residue of the estrogen receptor alpha (ER alpha) and influences the response of breast cancer cells to tamoxifen. We investigated the influence of Pak1 and pER alpha(ser305) on breast cancer prognosis and results of tamoxifen therapy. Experimental Design: We examined Pak1 and pER alpha(ser305) protein by immunohistochemistry in a series of 912 tumors from node-negative breast cancer patients randomized to tamoxifen or no adjuvant endocrine treatment. Results: Cytoplasmic Pak1 correlated to large tumors and ER negativity, whereas nuclear Pak1 and pER alpha(ser305) correlated to small tumors and ER positivity. Nuclear expression of Pak1 and pER alpha(ser305) predicted reduced response to tamoxifen in patients with ER alpha-positive tumors (tamoxifen versus no tamoxifen: hazard ratio (HR), 1.33; 95% confidence interval (95% CI), 0.42-4.2; P = 0.63), whereas patients lacking this combination benefitted significantly from tamoxifen (HR, 0.43; 95% CI, 0.30-0.62; P less than 0.0001). Similar nonsignificant trends were detected in analyses of the proteins separately. Pak1 in the cytoplasm was an independent prognostic marker, indicating increased recurrence rate (HR, 1.79; 95% CI, 1.17-2.74; P = 0.0068) and breast cancer mortality (HR, 1.98; 95% CI, 1.14-3.46; P = 0.016) for patients randomized to no adjuvant treatment. Conclusion: Our results suggest that patients with tumors expressing Pak1 and pER alpha(ser305) in combination are a group in which tamoxifen treatment is insufficient. In addition, the pathway may be of interest as a drug target in breast cancer. Furthermore, the findings support previous studies showing that Pak1 has differential roles in the cytoplasm and the nucleus.Original Publication:Josefine Bostner, Lambert Skoog, Tommy Fornander, Bo Nordenskjöld and Olle Stål, Estrogen Receptor-alpha Phosphorylation at Serine 305, Nuclear p21-Activated Kinase 1 Expression, and Response to Tamoxifen in Postmenopausal Breast Cancer, 2010, Clinical Cancer Research, (16), 5, 1624-1633.http://dx.doi.org/10.1158/1078-0432.CCR-09-1733Copyright: American Association for Cancer Research, Inc.http://www.aacr.org
Abstract P2-05-14: Prognostic impact of genomic risk stratification with breast cancer index in patients with clinically low risk, hormone receptor-positive, node-negative, T1 breast cancer
No full textAbstract
Background: Tumor size and nodal status are prognostic for risk of both early and late disease recurrence in patients with early stage, HR+ breast cancer, and are incorporated into both adjuvant chemotherapy and extended endocrine therapy treatment decisions. In a recent EBCTCG meta-analysis of over 46,000 patients [Pan H, et al. J Clin Oncol 34, 2016 (suppl; abstr 505)], risk of late distant recurrence was assessed in patient subsets based on nodal status and tumor size. Patients with T1N0 disease who were treated with 5 years endocrine therapy had a good overall prognosis, with 4%, 9%, and 14% risk of distant recurrence from years 5-10, 5-15, and 5-20, respectively. Breast Cancer Index (BCI) has been validated as prognostic biomarker for risk of both early and late distant recurrence in multiple randomized trial cohorts. The aim of this analysis was to assess distant recurrence (DR) risk stratification with BCI in patients with clinically low-risk T1N0 tumors.
Methods: Primary tumor samples from the subset of patients with T1N0 disease from 2 independent validation cohorts of HR+ breast cancer patients were examined [Stockholm randomized controlled trial (N=259) and a retrospective multi-institutional cohort (N=237)]. Patients in the Stockholm RCT cohort were treated with adjuvant tamoxifen only; patients in the multi-institutional cohort were treated with adjuvant tamoxifen +/- chemotherapy (20.3%). No patients received extended endocrine therapy. Kaplan-Meier analysis was used to assess the risk of DR within distinct BCI risk groups. Time dependent analysis was performed by combining BCI Low and Intermediate risk groups for risk of early recurrence (0-5y), and BCI Intermediate and High risk groups for risk of late recurrence (>5y).
Results: In the Stockholm cohort, BCI identified 13% of T1N0 patients as high risk for relapse within the first 5y, and these patients had a significantly reduced distant recurrence-free survival (DRFS, 85.3%) compared to BCI Low Risk patients (97.7%; P=0.0004). In patients disease-free at year 5, BCI identified 32% of patients as high risk for late recurrence; these patients had significantly lower DRFS (86.7%) between years 5-15 compared to BCI low risk patients (95.4%; P=0.0263). In the multi-institutional cohort, 22% of T1N0 patients were identified by BCI as high risk for relapse within the first 5y, and these patients had a significantly reduced DRFS (77.3%) compared to BCI low risk patients (96.2%; P<0.0001). In patients disease-free at year 5, 36% of patients were identified by BCI as high risk for late recurrence, with significantly lower DRFS (89.6%) between years 5-10 compared to BCI Low Risk patients (98.4%; P=0.008).
Conclusions: HR+ Patients with favorable clinical features (T1N0) have a good overall prognosis. However, results of this study demonstrated that adding molecular resolution on tumor biology with BCI identified a significant subset of women with higher risk of both early and late distant recurrence; findings support consideration of genomic classification in T1N0 patients to identify additional candidates for adjuvant chemotherapy and/or extended endocrine therapy, respectively.
Citation Format: Schroeder BE, Zhang Y, Stal O, Fornander T, Brufsky A, Sgroi DC, Schnabel CA. Prognostic impact of genomic risk stratification with breast cancer index in patients with clinically low risk, hormone receptor-positive, node-negative, T1 breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-14.</jats:p
The rehabilitation process after breast cancer diagnosis : factors of importance for return to work
No full textThe most common female cancer in Western countries is breast cancer and women diagnosed with this disease are often under 65 years old. With increasing prevalence of survivors it is important to shed light on problems facing these women after diagnosis and treatment. The overall aim of this thesis was to study the rehabilitation process following a breast cancer diagnosis for women at working age by examining factors related to type of treatment, tumour stage, socio-demographic status, health status, working condition, life satisfaction, and coping skills, and their association with return to work.In this thesis both quantitative and qualitative approaches are represented in three longitudinal cohort studies and a narrative interview study (16 enrolled women). The quantitative studies are based on two different sets of material of women treated for breast cancer (270 respective 102 enrolled women).Study I investigated whether factors such as type of treatment, tumour stage, educational level, matrimonial status, and presence of under-age children were associated with long-term problems in returning to work in women with breast cancer treated with endocrine therapy. The use of adjuvant endocrine therapy was associated with a twofold increase in the odds ratio of not having returned to work, although the confidence interval of this ratio was wide and included unity. Tumour stage (pN1-4+) was negatively associated with work status, possibly because of its association with adjuvant chemotherapy and radiotherapy to the regional nodes. Socio-demographic factors were not significantly associated with return to work.The aim of Study II was to identify factors contributing to a successful return to the labour market using the narratives of women treated for breast cancer. All the women strove to belong to the labour market, but the study also revealed how women´s perceptions of the value of employment changed. The quality of social support received from employers and co-workers differed between women who returned to work and those still sick-listed one year after breast cancer treatment.Study III investigated if treatment type, socio-demographic factors, health status, and work-related factors could predict return to work 10 months after surgery for early-stage breast cancer in women. Axillary node dissection, treatment with chemotherapy, and high demands at work were shown to play an important role in return to work for women with early-stage breast cancer. Socio-demographic factors were not significantly associated with return to work.The aims of Study IV were to generate new knowledge about life satisfaction, coping and rehabilitative measures taken after early-stage breast cancer treatment and the association of these concepts with return to work. Global life satisfaction was higher among the working women at both assessments. The working women used more positive coping resources compared with the sick-listed women, especially if treated with chemotherapy. Few of the sick-listed women received rehabilitation.The principal finding was that most of the studied women successfully returned to work after their active cancer treatments were completed. Type of treatment as well as work-related factors, life satisfaction and coping skills were associated with return to work.List of scientific papersI. Johnsson A, Fornander T, Olsson M, Nystedt M, Johansson H, Rutqvist LE (2007). "Factors associated with return to work after breast cancer treatment." Acta Oncol 46(1): 90-6. https://doi.org/10.1080/02841860600857318 II. Johnsson A, Fornander T, Rutqvist L, Olsson M (2008). "Factors influencing return to work: a narrative study of women treated for breast cancer." European Journal of Cancer Care. [Accepted] https://doi.org/10.1002/(SICI)1097-0142(19980815)83:43.0.CO;2-F III. Johnsson A, Fornander T, Rutqvist L, Vaez M, Alexanderson K, Olsson M (2008). "Predictors of return to work ten months after breast cancer surgery." Acts Oncologica. [Accepted] https://doi.org/10.1080/02841860802477899 IV. Johnsson A, Fornander T, Rutqvist L, Olsson M (2008). "Life and work changes the first year after breast cancer diagnosis." [Submitted]</p
Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial
No full textTo access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldThe purpose of this randomized study was to examine if goserelin concomitant to CMF-chemotherapy as adjuvant treatment for premenopausal breast cancer, protects the ovaries from premature failure. A total of 285 premenopausal breast cancer patients, in a randomized adjuvant trial (Zoladex in premenopausal patients (ZIPP)), were assigned to a study on ovarian function. Node positive patients were assigned to CMF-(cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy in addition to endocrine therapy. All patients were randomly assigned to receive 2 years of goserelin, goserelin plus tamoxifen, tamoxifen alone or no endocrine treatment. We studied, if menses were affected in the treatment groups, up to 36 months after randomization. One year after completed CMF- and endocrine therapy, 36% of the women in the goserelin group reported menses, compared to 7% in the goserelin plus tamoxifen group, 13% in the tamoxifen group and 10% of the controls. Among women treated with goserelin, there was a statistically significant increase in the proportion of menstruating women, 1 year after completed treatment compared to at 24 months of treatment (P = 0.006), in contrast to all other treatment groups, who were unchanged or more often amenorrheic. In our study, there is some evidence of protective effect of goserelin on ovarian function in CMF treated women. This effect was not observed in the combined tamoxifen and goserelin treatment
Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer
No full textThe mammalian target of rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation, and metabolism through translational control. RPS6KB1 (S6K1) and RPS6KB2 (S6K2) are situated in the commonly amplified 17q21-23 and 11q13 regions. S6K1 amplification and protein overexpression have earlier been associated with a worse outcome in breast cancer, but information regarding S6K2 is scarce. The aim of this study was to evaluate the prognostic and treatment predictive relevance of S6K1/S6K2 gene amplification, as well as S6K2 protein expression in breast cancer. S6K1/S6K2 gene copy number was determined by real-time PCR in 207 stage II breast tumors and S6K2 protein expression was investigated by immunohistochemistry in 792 node-negative breast cancers. S6K1 amplification/gain was detected in 10.7%/21.4% and S6K2 amplification/gain in 4.3%/21.3% of the tumors. S6K2 protein was detected in the nucleus (38%) and cytoplasm (76%) of the tumor cells. S6K1 amplification was significantly associated with HER2 gene amplification and protein expression. S6K2 amplification correlated significantly with high S6K2 mRNA levels, ER+ status and CCND1 amplification. S6K1 and S6K2 gene amplification was associated with a worse prognosis independent of HER2 and CCND1. S6K2 gain and nuclear S6K2 expression was related to an improved benefit from tamoxifen among patients with ER+, respectively ER+/PgR+ tumors. In the ER+/PgR- subgroup, nuclear S6K2 rather indicated decreased tamoxifen responsiveness. S6K1 amplification predicted reduced benefit from radiotherapy. This is the first study showing that S6K2 amplification and overexpression, like S6K1 amplification, have prognostic and treatment predictive significance in breast cancer.The original publication is available at www.springerlink.com: Gizeh Perez-Tenorio, Elin Karlsson, Marie Ahnström, Birgit Olsson, Birgitta Holmlund, Bo Nordenskjöld, Tommy Fornander, Lambert Skoog and Olle Stål, Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer, 2011, Breast Cancer Research and Treatment, (128), 3, 713-723. http://dx.doi.org/10.1007/s10549-010-1058-x Copyright: Springer Science Business Media http://www.springerlink.com
Structural Studies Using Polarized Light Spectroscopy and Isothermal Titration Calorimetry
No full textDNA is fundamental for all living cells; the DNA holds the genetic code, which is more or less the instruction book for how all cells are built and function. Several diseases are also linked to DNA, emerging either from a mutation in our genome, which could result in a malfunctioning protein, or that the transcription of genes is somehow affected by structural changes in the DNA, induced by mutations or DNA binding molecules. Research concerning how both small molecules and larger protein assemblies bind to the DNA are therefore of great interest since these could be used as future drugs in for example gene therapy.
In the first part of this Thesis the non-covalent binding to DNA of a small minor groove binder, Hoechst 33258, is examined. The molecule is rather well-studied, but there are still questions concerning its multiple binding modes to DNA sequences rich in adenines (A) and thymines (T) that remain unanswered. An increased understanding of the nature of the multiple binding modes could benefit the future design and development of sequence specific drugs. Using the thermodynamic characterization of the binding through Isothermal Titration Calorimetry (ITC) in combination with the spectroscopic properties of the formed complexes through Circular Dichroism (CD) we have analyzed the experimental results in a global dataset. We conclude that two molecules of Hoechst 33258 can bind next to each other in AT-rich sequences that consist of eight AT base pairs, but not in sequences consisting of six or less AT base pairs. They do not bind on top of one another, in the form of a sandwich, as previously proposed, nor contiguously, but with distinct separation between monomeric units.
The second part of this Thesis reports how the structure and activity of the human recombination protein RAD51 (HsRad51) depends on presence of cofactors: ATP and divalent cations. The eukaryotic HsRad51 is one of the evolutionarily best-conserved proteins and homologues to it can be found in both Bacteria and Archaea. HsRad51 is involved in the strand exchange reaction of homologous recombination, which takes place during meiosis and repair of double-strand breaks in eukaryotes. With further understanding of the strand exchange reaction we might find ways to utilize it in the medicinal field, such as for correction and repair of defective genes in gene therapy, or as a potential target in cancer treatment. We confirm that the first intermediate of this reaction, in which HsRad51 forms a helical filament around a single strand of DNA, demonstrates a perpendicular organization of the DNA bases relative the filament axis when ATP and Ca2+ are present. This organization is most probably related to the observed high strand exchange activity of the HsRad51/ssDNA complex in with ATP and Ca2+. By contrast, in presence of Mg2+ we observe both poor base organization and strand exchange activity
Cortical plasticity in response to median nerve trauma
No full textMedian nerve injuries in adults, repaired with nerve suture, lead to incomplete functional recovery despite improved surgical technique. This results in a reduction in quality of life, poorer working ability and a considerable expense for society. Misrouting of axons at the suture site connects regenerating axons to the wrong distal end organs. When distorted signals are conveyed to the dorsal root ganglia, spinal cord, thalamus and the somatosensory cortex, somatotopic maps at all levels become reorganised in a disorderly fashion. Children often regain full sensory function after median nerve injury and repair despite impaired conduction across the injured segment. There is growing evidence that cortical plasticity is the main mechanism behind the superior recovery seen in young patients, but the exact pattern of reorganisation and its impact on functional recovery are not fully understood.The general aim of this thesis was to investigate various aspects of cortical plasticity, in particular the response to median nerve injury. To this end we used two non-invasive brain imaging techniques, functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). In Paper I we investigated the concept of audio-tactile interaction in a healthy population. We found an increased overlap between cortical activation areas (fMRI) in patients trained with coupled tactile and auditory stimuli indicating modulation of cortical plasticity induced by cross-modal training.In Paper II we studied ageand time-dependent effects on cortical activity patterns in patients with median nerve injury by correlating age at the time of injury and time passed since injury to sensory function, and cortical activation. We found a time-dependent decline in the size of the cortical activation area during stimulation of both the median and the ulnar nerve (fMRI). Furthermore, there was greater ipsilateral activation in the patient group than in a control group from a previous study. However, the results were not conclusive on this point because the stimulation paradigms differed between the two studies (event-related in the present and block paradigm in the previous study).Paper III was performed using MEG in order to further study cortical plasticity in patients with median nerve injury. We found decreased N1 and P1 amplitudes during stimulation of the injured median nerve, and an increase in these amplitudes during ulnar nerve stimulation. Paper IV was designed to reveal any possible differences in lateralisation of cortical activation after median nerve injury and to see if this was influenced by the stimulus paradigm used. By means of a laterality index (LI) the extent of contra- and ipsilateral activation was calculated. LI is decreased (more ipsilateral activation) in patients with a median nerve injury compared to controls. This means that median nerve injury causes a shift of activity from the contralateral to the ipsilateral SI. The type of stimulus paradigm (event-related or block) did not affect LI. Our findings add to the evolving knowledge of the cortical plasticity following median nerve injury.List of scientific papersI. Lundborg G., Björkman A., Hansson T., Nylander L., Nyman T., Rosén B. Artificial sensibility of the hand based on cortical audiotactile interaction: a study using functional magnetic resonance imaging. Scandinavian journal of plastic and reconstructive surgery and hand surgery. 2005; 39:370-372. https://doi.org/10.1080/02844310500369920 II. Fornander L., Nyman T., Hansson T., Ragnehed M., Brismar T. Age- and time-dependent effects on functional outcome and cortical activation pattern in patients with median nerve injury: a functional magnetic resonance imaging study. Journal of Neurosurgery. 2010; 113, 122-128. https://doi.org/10.3171/2009.10.JNS09698 III. Fornander L, Brismar T, Hansson T, Wikström H. Cortical plasticity in patients with median nerve lesions studied with MEG. Somatosensory and Motor Research. 2016; 20, 1-8. https://doi.org/10.1080/08990220.2016.1230094 IV. Fornander L., Nyman T, Hansson T, Brismar T, Engström M. Interhemispheric plasticity in patients with median nerve injury. Neuroscience Letters. 2016; 15: 628:59-66. https://doi.org/10.1016/j.neulet.2016.06.018 </p
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