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Low expression levels of ATM may substitute for CHEK2 /TP53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer
Stian Knappskog, Ranjan Chrisanthar, Erik L?kkevik, Gun Anker, Bj?rn ?stenstad, Steinar Lundgren, Terje Risberg, Ingvil Mjaaland, Beryl Leirvaag, Hrvoje Miletic, Per E L?nning
Breast Cancer Research , 2012, DOI: 10.1186/bcr3147
Abstract: We sequenced ATM and assessed gene expression levels in pre-treatment biopsies from 71 locally advanced breast cancers treated in the neoadjuvant setting with doxorubicin monotherapy or mitomycin combined with 5-fluorouracil. Findings were confirmed in a separate patient cohort treated with epirubicin monotherapy. Each tumor was previously analyzed for CHEK2 and TP53 mutation status.While ATM mutations were not associated with chemo-resistance, low ATM expression levels predicted chemo-resistance among patients with tumors wild-type for TP53 and CHEK2 (P = 0.028). Analyzing the ATM-chk2-p53 cascade, low ATM levels (defined as the lower 5 to 50% percentiles) or mutations inactivating TP53 or CHEK2 robustly predicted anthracycline resistance (P-values varying between 0.001 and 0.027 depending on the percentile used to define "low" ATM levels). These results were confirmed in an independent cohort of 109 patients treated with epirubicin monotherapy. In contrast, ATM-levels were not suppressed in resistant tumors harboring TP53 or CHEK2 mutations (P > 0.5).Our data indicate loss of function of the ATM-Chk2-p53 cascade to be strongly associated with resistance to anthracycline/mitomycin-containing chemotherapy in breast cancer.Despite significant improvements in cancer therapy over the last decades, resistance towards chemotherapy remains the main obstacle to cure among patients suffering from solid tumors [1].The molecular mechanisms causing chemo-resistance in breast cancer, as for most other cancer forms, are poorly understood. While Topoisomerase-II amplified tumors on average reveal enhanced anthracycline sensitivity compared to non-amplified tumors [2-5], lack of Topoisomerase-II expression may not explain anthracycline resistance.p53, the tumor suppressor protein encoded by the TP53 gene, plays a key role with respect to apoptosis but also senescence, growth arrest and DNA repair [6,7]. Our group has previously linked mutations in TP53, (in particular those affect
CHEK2 Mutations Affecting Kinase Activity Together With Mutations in TP53 Indicate a Functional Pathway Associated with Resistance to Epirubicin in Primary Breast Cancer
Ranjan Chrisanthar, Stian Knappskog, Erik L?kkevik, Gun Anker, Bj?rn ?stenstad, Steinar Lundgren, Elisabet O. Berge, Terje Risberg, Ingvil Mjaaland, Lovise M?hle, Lars Fredrik Engebretsen, Johan Richard Lillehaug, Per Eystein L?nning
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003062
Abstract: Background Chemoresistance is the main obstacle to cure in most malignant diseases. Anthracyclines are among the main drugs used for breast cancer therapy and in many other malignant conditions. Single parameter analysis or global gene expression profiles have failed to identify mechanisms causing in vivo resistance to anthracyclines. While we previously found TP53 mutations in the L2/L3 domains to be associated with drug resistance, some tumors harboring wild-type TP53 were also therapy resistant. The aim of this study was; 1) To explore alterations in the TP53 gene with respect to resistance to a regular dose epirubicin regimen (90 mg/m2 every 3 week) in patients with primary, locally advanced breast cancer; 2) Identify critical mechanisms activating p53 in response to DNA damage in breast cancer; 3) Evaluate in vitro function of Chk2 and p14 proteins corresponding to identified mutations in the CHEK2 and p14(ARF) genes; and 4) Explore potential CHEK2 or p14(ARF) germline mutations with respect to family cancer incidence. Methods and Findings Snap-frozen biopsies from 109 patients collected prior to epirubicin (as preoperative therapy were investigated for TP53, CHEK2 and p14(ARF) mutations by sequencing the coding region and p14(ARF) promoter methylations. TP53 mutastions were associated with chemoresistance, defined as progressive disease on therapy (p = 0.0358; p = 0.0136 for mutations affecting p53 loop domains L2/L3). Germline CHEK2 mutations (n = 3) were associated with therapy resistance (p = 0.0226). Combined, mutations affecting either CHEK2 or TP53 strongly predicted therapy resistance (p = 0.0101; TP53 mutations restricted to the L2/L3 domains: p = 0.0032). Two patients progressing on therapy harbored the CHEK2 mutation, Arg95Ter, completely abrogating Chk2 protein dimerization and kinase activity. One patient (Epi132) revealed family cancer occurrence resembling families harboring CHEK2 mutations in general, the other patient (epi203) was non-conclusive. No mutation or promoter hypermethylation in p14(ARF) were detected. Conclusion This study is the first reporting an association between CHEK2 mutations and therapy resistance in human cancers and to document mutations in two genes acting direct up/down-stream to each other to cause therapy failure, emphasizing the need to investigate functional cascades in future studies.
Predictive and Prognostic Impact of TP53 Mutations and MDM2 Promoter Genotype in Primary Breast Cancer Patients Treated with Epirubicin or Paclitaxel
Ranjan Chrisanthar,Stian Knappskog,Erik L?kkevik,Gun Anker,Bj?rn ?stenstad,Steinar Lundgren,Terje Risberg,Ingvil Mjaaland,Gudbrand Skj?nsberg,Turid Aas,Ellen Schlichting,Hans E. Fj?sne,Arne Nysted,Johan Richard Lillehaug,Per Eystein L?nning
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019249
Abstract: TP53 mutations have been associated with resistance to anthracyclines but not to taxanes in breast cancer patients. The MDM2 promoter single nucleotide polymorphism (SNP) T309G increases MDM2 activity and may reduce wild-type p53 protein activity. Here, we explored the predictive and prognostic value of TP53 and CHEK2 mutation status together with MDM2 SNP309 genotype in stage III breast cancer patients receiving paclitaxel or epirubicin monotherapy.
Persistence of disseminated tumor cells after neoadjuvant treatment for locally advanced breast cancer predicts poor survival
Randi R Mathiesen, Elin Borgen, Anne Renolen, Erik L?kkevik, Jahn M Nesland, Gun Anker, Bj?rn ?stenstad, Steinar Lundgren, Terje Risberg, Ingvil Mjaaland, Gunnar Kvalheim, Per Eystein L?nning, Bj?rn Naume
Breast Cancer Research , 2012, DOI: 10.1186/bcr3242
Abstract: Bone marrow and peripheral blood were collected before NACT (BM1: n = 231/PB1: n = 219), at surgery (BM2: n = 69/PB2: n = 71), and after 12 months from start of NACT (BM3: n = 162/PB3: n = 141). Patients were included from 1997 to 2003 and followed until 2009 (or ten years follow-up). DTC- and CTC-status were determined by morphological evaluation of immunocytochemically detected cytokeratin-positive cells. The prognostic significance of DTCs/CTCs was assessed by univariate and multivariate Cox-regression analyses.Before NACT, DTCs and CTCs were detected in 21.2% and 4.9% of the patients, respectively. At surgery, 15.9% and 1.4% had DTC- and CTC-presence, compared to 26.5% and 4.3% at 12 months from start of NACT. Of patients for whom DTC results both before NACT and at 12 months were available, concordant results were observed in 68%, and 14 out of 65 had positive DTC-status at both time points. Presence of ≥ 1 DTC 12 months from start of NACT, but not at other time points, predicted reduced disease-free survival (DFS; HR 2.3, p = 0.003), breast cancer-specific survival (BCSS; HR 3.0, p < 0.001) and overall survival (OS; HR 2.8, p < 0.001). Before NACT, presence of ≥ 3 DTCs was also associated with unfavorable outcome, and reduced BCSS was observed for CTC-positive patients (HR 2.2, p = 0.046). In multivariate analysis, DTC status (
God and Passion in Kierkegaard's Climacus
Timmann Mjaaland, Marius
Ars Disputandi : the Online Journal for Philosophy of Religion , 2010,
Frequency of GP communication addressing the patient's resources and coping strategies in medical interviews: a video-based observational study
Trond A Mjaaland, Arnstein Finset
BMC Family Practice , 2009, DOI: 10.1186/1471-2296-10-49
Abstract: Twenty-four GPs were video-recorded in 145 consultations. The consultations were coded using a modified version of the Roter Interaction Analysis System. In this study, we also developed four additional coding categories based on cognitive therapy and solution-focused therapy: attribution, resources, coping, and solution-focused techniques.The reliability between coders was established, a factor analysis was applied to test the relationship between the communication categories, and a tentative validating exercise was performed by reversed coding.Cohen's kappa was 0.52 between coders. Only 2% of the utterances could be categorized as resource or coping oriented. Six GPs contributed 59% of these utterances. The factor analysis identified two factors, one task oriented and one patient oriented.The frequency of communication about coping and resources was very low. Communication skills training for GPs in this field is required. Further validating studies of this kind of measurement tool are warranted.Over the last few years, we have seen an increasing focus on patient centeredness and shared decision making in primary care [1]. The research literature has reported that these developments have a number of advantages in patient care, including greater satisfaction with the decision process, more realistic expectations, increased correlation between patient values and decisions, and more active participation in the decision-making process by a patient [2]. A common feature in these trends is the greater emphasis on patient involvement, in terms of both eliciting a patient's perspective, the active transfer of information, and greater emphasis on shared decision making.Patient involvement is further refined in the field of psychotherapy. Several current psychotherapeutic methods aim to help patients overcome and resolve problems by using a patient's own resources in different ways, e.g., solution-focused therapy [3].Our research group is involved in the development and ass
Caesarean section among referred and self-referred birthing women: a cohort study from a tertiary hospital, northeastern Tanzania
Ingvil K S?rbye, Siri Vangen, Olola Oneko, Johanne Sundby, Per Bergsj?
BMC Pregnancy and Childbirth , 2011, DOI: 10.1186/1471-2393-11-55
Abstract: We used data from 21,011 deliveries, drawn from the birth registry of a tertiary hospital in northeastern Tanzania, during 2000-07. Referral status was categorized as self-referred if the woman had bypassed or not accessed referral, or formally-referred if referred by a health worker. Because CS indications were insufficiently registered, we applied the Ten-Group Classification System to determine the CS rate by obstetric group and referral status. Associations between referral status and adverse outcomes after CS delivery were analysed using multiple regression models. Outcome measures were CS, maternal death, obstetric haemorrhage ≥ 750 mL, postpartum stay > 9 days, neonatal death, Apgar score < 7 at 5 min and neonatal ward transfer.Referral status contributed substantially to the CS rate, which was 55.0% in formally-referred and 26.9% in self-referred birthing women. In both groups, term nulliparous singleton cephalic pregnancies and women with previous scar(s) constituted two thirds of CS deliveries. Low Apgar score (adjusted OR 1.42, 95% CI 1.09-1.86) and neonatal ward transfer (adjusted OR 1.18, 95% CI 1.04-1.35) were significantly associated with formal referral. Early neonatal death rates after CS were 1.6% in babies of formally-referred versus 1.2% in babies of self-referred birthing women, a non-significant difference after adjusting for confounding factors (adjusted OR 1.37, 95% CI 0.87-2.16). Absolute neonatal death rates were > 2% after CS in breech, multiple gestation and preterm deliveries in both referral groups.Women referred for delivery had higher CS rates and poorer neonatal outcomes, suggesting that the formal referral system successfully identifies high-risk birth, although low volume suggests underutilization. High absolute rates of post-CS adverse outcomes among breech, multiple gestation and preterm deliveries suggest the need to target self-referred birthing women for earlier professional intrapartum care.Progress towards Millennium Develop
Teamwork skills, shared mental models, and performance in simulated trauma teams: an independent group design
Heidi Westli, Bj?rn Johnsen, Jarle Eid, Ingvil Rasten, Guttorm Bratteb?
Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine , 2010, DOI: 10.1186/1757-7241-18-47
Abstract: Revised versions of the 'Anesthetists' Non-Technical Skills Behavioural marker system' and 'Anti-Air Teamwork Observation Measure' were field tested in moment-to-moment observation of 27 trauma team simulations in Norwegian hospitals. Independent subject matter experts rated medical management in the teams. An independent group design was used to explore differences in teamwork skills between higher-performing and lower-performing teams.Specific teamwork skills and behavioural markers were associated with indicators of good team performance. Higher and lower-performing teams differed in information exchange, supporting behaviour and communication, with higher performing teams showing more effective information exchange and communication, and less supporting behaviours. Behavioural markers of shared mental models predicted effective medical management better than teamwork skills.The present study replicates and extends previous research by providing new empirical evidence of the significance of specific teamwork skills and a shared mental model for the effective medical management of trauma teams. In addition, the study underlines the generic nature of teamwork skills by demonstrating their transferability from different clinical simulations like the anaesthesia environment to trauma care, as well as the potential usefulness of behavioural frequency analysis in future research on non-technical skills.Members of trauma teams are expected to share a common goal, and to synchronise individual skills in interdependent collaboration in order to provide safe and efficient patient care [1]. Although team members are sufficiently trained individually, teamwork skills have traditionally been less emphasised in medical training [2]. The knowledge that fatal errors due to 'human factors' can occur in 70-80% of medical mishaps has led to growing interest in medical teams' cognitive and interpersonal skills, such as leadership and communication, which are referred to as 'non-tech
Weekly Paclitaxel plus Capecitabine versus Docetaxel Every 3 Weeks plus Capecitabine in Metastatic Breast Cancer
E. A. Wist,I. Mjaaland,E. L kkevik,H. H. Sommer
Journal of Oncology , 2012, DOI: 10.1155/2012/862921
Abstract: Background. We performed a randomized phase II study comparing efficacy and toxicity of weekly paclitaxel 80 mg/m2 (Weetax) with three weekly docetaxel 75 mg/m2 (Threetax), both in combination with oral capecitabine 1000 mg/m2 twice daily for 2 weeks followed by a 1-week break. Patients. Thirty-seven women with confirmed metastatic breast cancer were randomized. Results. Median TTF was 174 (Weetax) versus 147 days (Threetax) (=0.472). Median OS was 933 (Weetax) versus 464 days (Threetax) (=0.191). Reasons for TTF were PD 8/18 (Weetax), 9/19 (Threetax); and toxicity: 8/18 (Weetax), 8/19 (Threetax). ORR was 72% (Weetax) versus 26% (Threetax) (=0.01). The Threetax-combination resulted in a higher incidence of leuco-/neutropenia compared to Weetax. Grade II anemia was more pronounced in the Weetax group. No difference was found in quality of life. Conclusion. Taxanes in combination with capecitabine resulted in a high level of toxicity. Taxanes and capecitabine should be considered given sequentially and not in combination.
Analysis of host- and strain-dependent cell death responses during infectious salmon anemia virus infection in vitro
Berit L Schi?tz, Espen S B?kkevold, Lene C Poulsen, Siri Mjaaland, Tor Gj?en
Virology Journal , 2009, DOI: 10.1186/1743-422x-6-91
Abstract: The results show that caspase 3/7 activity increased during the course of infection in ASK and SHK-1 cells, infected cells showed increased surface expression of phosphatidylserine and increased PI uptake, compared to mock infected cells; and morphological alterations of the mitochondria were observed. Expression analysis of immune relevant genes revealed no correlation between in vivo mortality and expression, but good correlation in expression of interferon genes.Results from this study indicate that there is both strain and cell type dependent differences in the virus-host interaction during ISAV infection. This is important to bear in mind when extrapolating in vitro findings to the in vivo situation.Infectious salmon anemia virus is an aquatic orthomyxovirus of the genus Isavirus [1]. ISAV is the causative agent of infectious salmon anemia (ISA), an emerging disease causing high mortalities and great economic losses in the Atlantic salmon (Salmo salar L.) farming industry. Large differences in disease severity and clinical signs are observed both in field outbreaks [2-5] and experimental trials [6-11]. Affected fish are often anemic; other typical findings are haemorrhagic liver necrosis, ascites and petechiae in the viscera [12]. The virus is reported to cause acute or protracted disease in fish in vivo [6]. Several strains of ISAV are known and categorized according to the highly polymorphic region of the hemagglutinin-esterase protein, and according to the ability of the virus to induce acute versus protracted disease in affected fish. Although much is known about the structure and genetics of the virus, less is known about the immune reactions induced by ISAV. In vitro, ISAV replicates and causes cytophatic effect. We wanted to investigate the mode of cell death and transcriptional changes after in vitro infection. We also wanted to compare stress responses induced by four different Norwegian strains of ISAV. It has previously been shown that the mechanism
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