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Search Results: 1 - 10 of 143367 matches for " Marjanka K Schmidt "
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Familial versus Sporadic Breast Cancer: Different Treatments for Similar Tumors?  [PDF]
Ellen G. Engelhardt, Mieke Kriege, Maartje J. Hooning, Caroline Seynaeve, Rob A. E. M. Tollenaar, Christina J. van Asperen, Margreet G. E. M. Ausems, Lonneke V. van de Poll-Franse, Stella Mook, Senno Verhoef, Matti A. Rookus, HEBON Collaborators, Marjanka K. Schmidt
Advances in Breast Cancer Research (ABCR) , 2015, DOI: 10.4236/abcr.2015.44010
Abstract: Objective: It is unclear if and to what extent family history of breast/ovarian cancer or BRCA1/2-mutation carriership influences breast cancer treatment strategy. We investigated whether treatment differed between patients from BRCA1/2 families and those unselected for family history. Methods: We included 478 BRCA1/2-related patients referred for genetic testing before or after diagnosis. Two references were used: 13,498 population-based and 6896 hospital-based patients. Surgical treatment and adjuvant chemotherapy use was analyzed using logistic regression models, stratified by tumor size, nodal status, age at and period of diagnosis, and estrogen receptor status (ER). Results: BRCA1/2 cases aged 35 - 52 years at diagnosis and/or with tumors < 2 cm were more likely to have undergone a modified radical mastectomy (Odd Ratios (OR) ranging from 2.8 to 5.1) compared to the references. This effect was most pronounced in patients treated after 1995 (OR 5.7 to 10.3). Compared to the reference groups, chemotherapy was more often administered to BRCA1 and ER-negative BRCA1/2-cases irrespective of age and nodal status (OR 1.9 to 24.3). Conclusion: After 1995 treatment of BRCA1/2-associated patients consisted notably of more mastectomies and adjuvant chemotherapy than their population-based counterparts with the same tumor characteristics. There is a need to be aware of such differences in daily practice and interpretation of survival studies on BRCA1/2 mutation carriers.
Combined effects of single nucleotide polymorphisms TP53 R72P and MDM2 SNP309, and p53 expression on survival of breast cancer patients
Marjanka K Schmidt, Johanna Tommiska, Annegien Broeks, Flora E van Leeuwen, Laura J Van't Veer, Paul DP Pharoah, Douglas F Easton, Mitul Shah, Manjeet Humphreys, Thilo D?rk, Scarlett A Reincke, Rainer Fagerholm, Carl Blomqvist, Heli Nevanlinna
Breast Cancer Research , 2009, DOI: 10.1186/bcr2460
Abstract: We pooled data from four breast cancer cohorts within the Breast Cancer Association Consortium for which both TP53 R72P and MDM2 SNP309 were genotyped and follow-up was available (n = 3,749). Overall and breast cancer-specific survival analyses were performed using Kaplan-Meier analysis and multivariate Cox's proportional hazards regression models.Survival of patients did not differ by carriership of either germ-line variant, R72P (215G>C) or SNP309 (-410G>T) alone. Immunohistochemical p53 staining of the tumor was available for two cohorts (n = 1,109 patients). Survival was worse in patients with p53-positive tumors (n = 301) compared to patients with p53-negative tumors (n = 808); breast cancer-specific survival: HR 1.6 (95% CI 1.2 to 2.1), P = 0.001. Within the patient group with p53-negative tumors, TP53 rare homozygous (CC) carriers had a worse survival than G-allele (GG/GC) carriers; actuarial breast cancer-specific survival 71% versus 80%, P = 0.07; HR 1.8 (1.1 to 3.1), P = 0.03. We also found a differential effect of combinations of the two germ-line variants on overall survival; homozygous carriers of the G-allele in MDM2 had worse survival only within the group of TP53 C-allele carriers; actuarial overall survival (GG versus TT/TG) 64% versus 75%, P = 0.001; HR (GG versus TT) 1.5 (1.1 to 2.0), P = 0.01. We found no evidence for a differential effect of MDM2 SNP309 by p53 protein expression on survival.The TP53 R72P variant may be an independent predictor for survival of patients with p53-negative tumors. The combined effect of TP53 R72P and MDM2 SNP309 on survival is in line with our a priori biologically-supported hypothesis, that is, the role of enhanced DNA repair function of the TP53 Pro-variant, combined with increased expression of the Mdm2 protein, and thus overall attenuation of the p53 pathway in the tumor cells.Breast cancer outcome may be affected by germ-line variants in genes that play a role in DNA damage control and repair such as TP53 (R72P
Identification of women with an increased risk of developing radiation-induced breast cancer: a case only study
Annegien Broeks, Linde M Braaf, Angelina Huseinovic, Anke Nooijen, Jos Urbanus, Frans BL Hogervorst, Marjanka K Schmidt, Jan GM Klijn, Nicola S Russell, Flora E Van Leeuwen, Laura J Van 't Veer
Breast Cancer Research , 2007, DOI: 10.1186/bcr1668
Abstract: We evaluated the contribution of germline mutations in the DDRP genes BRCA1, BRCA2, CHEK2 and ATM to the risk of radiation-induced contralateral breast cancer (CBC). The germline mutation frequency was assessed, in a case-only study, in women who developed a CBC after they had a first breast cancer diagnosed before the age of 50 years, and who were (n = 169) or were not (n = 78) treated with radiotherapy for their first breast tumour.We identified 27 BRCA1, 5 BRCA2, 15 CHEK2 and 4 truncating ATM germline mutation carriers among all CBC patients tested (21%). The mutation frequency was 24.3% among CBC patients with a history of radiotherapy, and 12.8% among patients not irradiated for the first breast tumour (odds ratio 2.18 (95% confidence interval 1.03 to 4.62); p = 0.043). The association between DDRP germline mutation carriers and risk of radiation-induced CBC seemed to be strongest in women who developed their second primary breast tumour at least 5 years after radiotherapy. Those patients had an odds ratio of 2.51 (95% confidence interval 1.03 to 6.10; p = 0.049) of developing radiation-induced breast cancer, in comparison with non-carriers.This study shows that carriers of germline mutations in a DDRP gene have an increased risk of developing (contralateral) breast cancer after radiotherapy; that is, over and above the risk associated with their carrier status. The increased risk indicates that knowledge of germline status of these DDRP genes at the time of breast cancer diagnosis may have important implications for the choice of treatment.Several risk factors for the development of breast cancer, such as family history, reproductive factors and exposure to radiation, have been identified. Out of all breast cancers, 5 to 10% can be attributed to germline mutations in familial high-risk genes such as BRCA1 or BRCA2 that result in a lifetime breast cancer risk of about 45 to 65% [1]. The penetrance varies between families, depending on 'risk modifiers' such as h
ATBF1 and NQO1 as candidate targets for allelic loss at chromosome arm 16q in breast cancer: Absence of somatic ATBF1 mutations and no role for the C609T NQO1 polymorphism
Anne-Marie Cleton-Jansen, Ronald van Eijk, Marcel Lombaerts, Marjanka K Schmidt, Laura J Van't Veer, Katja Philippo, Rhyenne ME Zimmerman, Johannes L Peterse, Vincent TBHM Smit, Tom van Wezel, Cees J Cornelisse
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-105
Abstract: A cDNA microarray for the 16q region was constructed and analyzed using RNA samples from 39 breast tumors with known LOH status at 16q.Five genes were identified to show lower expression in tumors with LOH at 16q compared to tumors without LOH. The genes for NAD(P)H dehydrogenase quinone (NQO1) and AT-binding transcription factor 1 (ATBF1) were further investigated given their functions as potential TSGs. NQO1 has been implicated in carcinogenesis due to its role in quinone detoxification and in stabilization of p53. One inactive polymorphic variant of NQO1 encodes a product showing reduced enzymatic activity. However, we did not find preferential targeting of the active NQO1 allele in tumors with LOH at 16q. Immunohistochemical analysis of 354 invasive breast tumors revealed that NQO1 protein expression in a subset of breast tumors is higher than in normal epithelium, which contradicts its proposed role as a tumor suppressor gene.ATBF1 has been suggested as a target for LOH at 16q in prostate cancer. We analyzed the entire coding sequence in 48 breast tumors, but did not identify somatic sequence changes. We did find several in-frame insertions and deletions, two variants of which were reported to be somatic pathogenic mutations in prostate cancer. Here, we show that these variants are also present in the germline in 2.5% of 550 breast cancer patients and 2.9% of 175 healthy controls. This indicates that the frequency of these variants is not increased in breast cancer patients. Moreover, there is no preferential LOH of the wildtype allele in breast tumors.Two likely candidate TSGs at 16q in breast cancer, NQO1 and ATBF1, were identified here as showing reduced expression in tumors with 16q LOH, but further analysis indicated that they are not target genes of LOH. Furthermore, our results call into question the validity of the previously reported pathogenic variants of the ATBF1 gene.Chromosome arm 16q is one of the regions most frequently involved in loss of heter
An Information-Theoretic Analysis of Genetics, Gender and Age in Cancer Patients
Gurinder Singh Atwal, Raúl Rabadán, Guillermina Lozano, Louise C. Strong, Mari?lle W. G. Ruijs, Marjanka K. Schmidt, Laura J. van't Veer, Heli Nevanlinna, Johanna Tommiska, Kristiina Aittom?ki, Gaelle Bougeard, Thierry Frebourg, Arnold J. Levine, Gareth L. Bond
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001951
Abstract: Germline genetics, gender and hormonal-signaling pathways are all well described modifiers of cancer risk and progression. Although an improved understanding of how germline genetic variants interact with other cancer risk factors may allow better prevention and treatment of human cancer, measuring and quantifying these interactions is challenging. In other areas of research, Information Theory has been used to quantitatively describe similar multivariate interactions. We implemented a novel information-theoretic analysis to measure the joint effect of a high frequency germline genetic variant of the p53 tumor suppressor pathway (MDM2 SNP309 T/G) and gender on clinical cancer phenotypes. This analysis quantitatively describes synergistic interactions among gender, the MDM2 SNP309 locus, and the age of onset of tumorigenesis in p53 mutation carriers. These results offer a molecular and genetic basis for the observed sexual dimorphism of cancer risk in p53 mutation carriers and a model is proposed that suggests a novel cancer prevention strategy for p53 mutation carriers.
Subtyping of Breast Cancer by Immunohistochemistry to Investigate a Relationship between Subtype and Short and Long Term Survival: A Collaborative Analysis of Data for 10,159 Cases from 12 Studies
Fiona M. Blows equal contributor,Kristy E. Driver equal contributor,Marjanka K. Schmidt,Annegien Broeks,Flora E. van Leeuwen,Jelle Wesseling,Maggie C. Cheang,Karen Gelmon,Torsten O. Nielsen,Carl Blomqvist,P?ivi Heikkil?,Tuomas Heikkinen,Heli Nevanlinna,Lars A. Akslen,Louis R. Bégin,William D. Foulkes,Fergus J. Couch,Xianshu Wang,Vicky Cafourek,Janet E. Olson,Laura Baglietto,Graham G. Giles,Gianluca Severi,Catriona A. McLean,Melissa C. Southey,Emad Rakha,Andrew R. Green,Ian O. Ellis,Mark E. Sherman,Jolanta Lissowska,William F. Anderson,Angela Cox,Simon S. Cross,Malcolm W. R. Reed,Elena Provenzano,Sarah-Jane Dawson,Alison M. Dunning,Manjeet Humphreys,Douglas F. Easton,Montserrat García-Closas,Carlos Caldas,Paul D. Pharoah ,David Huntsman
PLOS Medicine , 2010, DOI: 10.1371/journal.pmed.1000279
Abstract: Background Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. The aim of this study was to estimate mortality for patients with the major subtypes of breast cancer as classified using five immunohistochemical markers, to investigate patterns of mortality over time, and to test for heterogeneity by subtype. Methods and Findings We pooled data from more than 10,000 cases of invasive breast cancer from 12 studies that had collected information on hormone receptor status, human epidermal growth factor receptor-2 (HER2) status, and at least one basal marker (cytokeratin [CK]5/6 or epidermal growth factor receptor [EGFR]) together with survival time data. Tumours were classified as luminal and nonluminal tumours according to hormone receptor expression. These two groups were further subdivided according to expression of HER2, and finally, the luminal and nonluminal HER2-negative tumours were categorised according to expression of basal markers. Changes in mortality rates over time differed by subtype. In women with luminal HER2-negative subtypes, mortality rates were constant over time, whereas mortality rates associated with the luminal HER2-positive and nonluminal subtypes tended to peak within 5 y of diagnosis and then decline over time. In the first 5 y after diagnosis the nonluminal tumours were associated with a poorer prognosis, but over longer follow-up times the prognosis was poorer in the luminal subtypes, with the worst prognosis at 15 y being in the luminal HER2-positive tumours. Basal marker expression distinguished the HER2-negative luminal and nonluminal tumours into different subtypes. These patterns were independent of any systemic adjuvant therapy. Conclusions The six subtypes of breast cancer defined by expression of five markers show distinct behaviours with important differences in short term and long term prognosis. Application of these markers in the clinical setting could have the potential to improve the targeting of adjuvant chemotherapy to those most likely to benefit. The different patterns of mortality over time also suggest important biological differences between the subtypes that may result in differences in response to specific therapies, and that stratification of breast cancers by clinically relevant subtypes in clinical trials is urgently required. Please see later in the article for the Editors' Summary
Ukrain – a new cancer cure? A systematic review of randomised clinical trials
E Ernst, K Schmidt
BMC Cancer , 2005, DOI: 10.1186/1471-2407-5-69
Abstract: Seven electronic databases were searched for all relevant randomised clinical trials. Data were extracted and validated by both authors, tabulated and summarised narratively. The methodological quality was assessed with the Jadad score.Seven trials met our inclusion criteria. Without exception, their findings suggest that Ukrain has curative effects on a range of cancers. However, the methodological quality of most studies was poor. In addition, the interpretation of several trials was impeded by other problems.The data from randomised clinical trials suggest Ukrain to have potential as an anticancer drug. However, numerous caveats prevent a positive conclusion, and independent rigorous studies are urgently needed.Ukrain (NSC-631570) is a semi-synthetic compound derived from the common weed, greater celandine (Chelidonium majus L.). This plant contains a range of alkaloids, most notably chelidonine, also known as benzophenanthridine alkaloid. A leaflet distributed to patients at the Bristol Cancer Help Centre, United Kingdom, describes Ukrain as " the only known product, which at present does not also destroy healthy cells, and which reduces tumors and boosts the immune system..." [1]. Ukrain is most commonly administered intravenously and consists of one molecule thiophosphoric acid conjugated to three molecules of chelidonine. It has drug licenses in several states of the former Soviet Union.Research on Ukrain started about 20 years ago. Meanwhile, numerous in-vitro studies [2-37] animal experiments [38-83], case reports [84-97], and case series [98-108] have emerged. Collectively, these data suggest that Ukrain has anticancer activity in a wide range of cell lines, which could be of clinical value. Whether or not this translates into clinical effectiveness and whether or not Ukrain does indeed cure some type of cancer or improves their prognosis can best be decided on the basis of randomised clinical trials (RCTs). This systematic review is aimed at summarising a
Poincaré maps of Duffing--type oscillators and their reduction to circle maps. I. Analytic results
G. Eilenberger,K. Schmidt
Physics , 1993,
Abstract: Bifurcation diagrams and plots of Lyapunov exponents in the $r$--$\Omega$ --plane for Duffing--type oscillators $$\ddot x +2r\dot x +V'(x,\Omega t) =0$$ exhibit a regular pattern of repeating selfsimilar ``tongues'' with complex internal structure. We demonstrate here that this behaviour is easily understood qualitatively and quantitatively from the Poincar\'e map of the system in action--angle variables. This map approaches the {\it one dimensional} form $$\varphi_{n+1} = A + C \e^{-r T} \cos \varphi_n, \ \ T= \pi / \Omega$$ provided $\e^{-r T}$ (but not necessarily $C \e^{- r T}$), $r$ and $\Omega$ are small. We derive asymptotic (for $r$, $\Omega$ small) formulae for $A$ and $C$ for a special class of potentials $V$. We argue that these special cases contain all the information needed to treat the general case of potentials which obey $V'' \ge 0$ at all times. The essential tools of the derivation are the use of action--angle variables, the adiabatic approximation and the introduction of a nonoscillating reference solution of Duffing's equation, with respect to which the action-angle variables have to be determined. These allow the explicit construction of the Poincar\'e map in powers of $\e^{-rT}$. To first order, we obtain the $\varphi$--map, which survives asymptotically. To {\it second} order we obtain the two--dimensional $I$--$\varphi$--map. In $I$--direction it contracts by a factor $\e^{-rT}$ upon each iteration.
About the inconsistency between Bohr-Wheelers transition-state method and Kramers' escape rate in nuclear fission
K. -H. Schmidt
Physics , 2008, DOI: 10.1142/S0218301309012951
Abstract: The problem of an apparent inconsistency between the fission rates derived on the basis of Bohr-Wheeler's transition-state method and Kramers' dynamical model of nuclear fission, first pointed out by Strutinsky in 1973, is revisited. The study is based on studying the features of individual trajectories on the fission path.
Persisting topological order via geometric frustration
K. P. Schmidt
Physics , 2013, DOI: 10.1103/PhysRevB.88.035118
Abstract: We introduce a toric code model on the dice lattice which is exactly solvable and displays topological order at zero temperature. In the presence of a magnetic field, the flux dynamics is mapped to the highly frustrated transverse field Ising model on the kagome lattice. This correspondence suggests an intriguing disorder by disorder phenomenon in a topologically ordered system implying that the topological order is extremely robust due to the geometric frustration. Furthermore, a connection between fully frustrated transverse field Ising models and topologically ordered systems is demonstrated which opens an exciting physical playground due to the interplay of topological quantum order and geometric frustration.
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