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Histopathological features of breast tumours in BRCA1, BRCA2 and mutation-negative breast cancer families
Hannaleena Eerola, P?ivi Heikkil?, Anitta Tamminen, Kristiina Aittom?ki, Carl Blomqvist, Heli Nevanlinna
Breast Cancer Research , 2004, DOI: 10.1186/bcr953
Abstract: Breast cancer tissue specimens (n = 262) from 25 BRCA1, 20 BRCA2 and 74 non-BRCA1/2 families were studied on a tumour tissue microarray. Immunohistochemical staining of oestrogen receptor (ER), progesterone receptor (PgR) and p53 as well as the histology and grade of these three groups were compared with each other and with the respective information on 862 unselected control patients from the archives of the Pathology Department of Helsinki University Central Hospital. Immunohistochemical staining of erbB2 was also performed among familial cases.BRCA1-associated cancers were diagnosed younger and were more ER-negative and PgR-negative, p53-positive and of higher grade than the other tumours. However, in multivariate analysis the independent factors compared with non-BRCA1/2 tumours were age, grade and PgR negativity. BRCA2 cases did not have such distinctive features compared with non-BRCA1/2 tumours or with unselected control tumours. Familial cases without BRCA1/2 mutations had tumours of lower grade than the other groups.BRCA1 families differed from mutation-negative families by age, grade and PgR status, whereas ER status was not an independent marker.Women predisposed to hereditary or familial breast cancer form a heterogeneous group. It would be useful if we could identify carriers of the high-risk BRCA1 and BRCA2 genes and target the expensive and time-consuming genetic testing to individuals who most probably carry those mutations. Besides family history, histopathological markers could also be useful in distinguishing patients and families likely to carry a BRCA1/2 germline mutation from mutation-negative families and breast cancer patients in general.Several studies have compared the characteristics of breast cancers in BRCA1 carriers and in sporadic controls. Distinct features between BRCA1-associated tumours have been found, such as high tumour grade, oestrogen receptor (ER) negativity, and overexpression of p53 [1-3]. In addition, negativity for proges
Application of the multicellular tumour spheroid model to screen PET tracers for analysis of early response of chemotherapy in breast cancer
Azita Monazzam, Raymond Josephsson, Carl Blomqvist, J?rgen Carlsson, Bengt L?ngstr?m, Mats Bergstr?m
Breast Cancer Research , 2007, DOI: 10.1186/bcr1747
Abstract: MTS of the breast cancer cell line MCF7 were exposed to doxorubicin, paclitaxel, docetaxel, tamoxifen or imatinib for 7 days for growth pattern studies and for 3 or 5 days for PET tracer studies. The effect on growth was computed using the semi-automated size determination method (SASDM). The effect on the uptake of PET tracers [18F]3'-deoxy-3'-fluorothymidine (FLT), [1-11C]acetate (ACE), [11C]choline (CHO), [11C]methionine (MET), and 2-[18F]fluoro-2-deoxyglucose (FDG) was calculated in form of uptake/viable volume of the MTS at the end of the drug exposures, and finally the uptake was related to effects on growth rate.The drugs paclitaxel, docetaxel and doxorubicin gave severe growth inhibition, which correlated well with inhibition of the FLT uptake. FLT had, compared with ACE, CHO, MET and FDG, higher sensitivity in monitoring the therapy effects.SASDM provides an effective, user-friendly, time-saving and accurate method to record the growth pattern of the MTS, and also to calculate the effect of the drug on PET tracer uptake. This study demonstrate the use of MTS and SASDM in combination with PET tracers as a promising approach to probe and select PET tracer for treatment monitoring of anticancer drugs and that can hopefully be applied for optimisation in breast cancer treatment.Positron emission tomography (PET) has demonstrated usefulness in monitoring therapeutic response in a wide range of cancers, including breast cancer [1,2]. This is because effective therapy leads to rapid physiological modification in tumours; with the right choice of PET tracer, this modification can easily be revealed and the therapeutic response can be clarified [3]. Physicians can thus quickly modify less effective therapy, thereby improving patient outcomes and reducing the cost of ineffective treatment.To date, 2-[18F]fluoro-2-deoxyglucose (FDG) has been the most common PET tracer; however future applications of PET will likely involve other tracers to improve characterisation of
Relationship of patients' age to histopathological features of breast tumours in BRCA1 and BRCA2 and mutation-negative breast cancer families
Hannaleena Eerola, P?ivi Heikkil?, Anitta Tamminen, Kristiina Aittom?ki, Carl Blomqvist, Heli Nevanlinna
Breast Cancer Research , 2005, DOI: 10.1186/bcr1025
Abstract: Representative areas of all available breast cancer tissue specimens (n = 262) from 25 BRCA1, 20 BRCA2, and 74 non-BRCA1/2 breast cancer families were punched into a tissue microarray. Immunohistochemical staining of oestrogen receptor, progesterone receptor, ERBB2, and p53 as well as the histology and grade of tumours in these three groups of families were studied in different age groups and compared with each other.We found that only breast cancers from young (<50 years) BRCA1+ patients represent features documented as being typical of BRCA1-associated cancers, such as high tumour grade, negativity for oestrogen and progesterone receptors, and overexpression of p53. Among the BRCA2 families, the opposite was found, with a significantly higher frequency of tumours negative for oestrogen and progesterone receptors among the older patients than among the other groups, but no distinctive tumour characteristics among the younger BRCA2 patients.Tumours of BRCA1 and BRCA2 carriers aged 50 years or more differed significantly from those of younger carriers. This difference may reflect different biological behaviour and pathways of tumour development among the older and the younger BRCA1 and BRCA2 patients, with impact also on prognosis and survival.Distinct pathological features among BRCA1-associated tumours have been found when such tumours are compared with sporadic cancers; these features include high tumour grade, negativity for oestrogen receptor (ER), overexpression of p53, negativity for progesterone receptor (PR), and a higher proportion of medullary and atypical medullary carcinomas [1-3]. Recently, cDNA expression analyses have suggested a basal epithelial phenotype for BRCA1 tumors [4] and expression of cytokeratins 5/6 have been associated with BRCA1 tumours [5]. Among BRCA2-associated tumours, findings have been inconsistent, and in most cases no significant difference has been found between BRCA2-associated and sporadic cancers [1,2,6,7].In our previous rep
BACH1 Ser919Pro variant and breast cancer risk
Pia Vahteristo, Kristiina Yliannala, Anitta Tamminen, Hannaleena Eerola, Carl Blomqvist, Heli Nevanlinna
BMC Cancer , 2006, DOI: 10.1186/1471-2407-6-19
Abstract: In this study, we aimed to evaluate whether there are BACH1 genetic variants that contribute to breast cancer risk in Finland.The BACH1 gene was screened for germ line alterations among probands from 43 Finnish BRCA1/2 negative breast cancer families. Recently, one of the observed common variants, Ser-allele of the Ser919Pro polymorphism, was suggested to associate with an increased breast cancer risk, and was here evaluated in an independent, large series of 888 unselected breast cancer patients and in 736 healthy controls.Six BACH1 germ line alterations were observed in the mutation analysis, but none of these were found to associate with the cancer phenotype. The Val193Ile variant that was seen in only one family was further screened in an independent series of 346 familial breast cancer cases and 183 healthy controls, but no additional carriers were observed. Individuals with the BACH1 Ser919-allele were not found to have an increased breast cancer risk when the Pro/Ser heterozygotes (OR 0.90; 95% CI 0.70–1.16; p = 0.427) or Ser/Ser homozygotes (OR 1.02; 95% CI 0.76–1.35; p = 0.91) were compared to Pro/Pro homozygotes, and there was no association of the variant with any breast tumor characteristics, age at cancer diagnosis, family history of cancer, or survival.Our results suggest that the BACH1 Ser919 is not a breast cancer predisposition allele in the Finnish study population. Together with previous studies, our results also indicate that although some rare germ line variants in BACH1 may contribute to breast cancer development, the contribution of BACH1 germline alterations to familial breast cancer seems marginal.BACH1 (BRCA1-associated C-terminal helicase 1, also known as BRCA1-interacting protein 1, BRIP1; GenBank: NM_032043) belongs to a DEAH helicase family and interacts in vivo with BRCA1, the protein product of one of the two major genes for hereditary breast cancer susceptibility [1,2]. Interaction is mediated through BRCT domains of BRCA1, motifs th
Comprehensive analysis of NuMA variation in breast cancer
Outi Kilpivaara, Matias Rantanen, Anitta Tamminen, Kristiina Aittom?ki, Carl Blomqvist, Heli Nevanlinna
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-71
Abstract: In order to evaluate the NuMa gene for breast cancer susceptibility, we have here screened the entire coding region and exon-intron boundaries of NuMa in 92 familial breast cancer patients and constructed haplotypes of the identified variants. Five missense variants were further screened in 341 breast cancer cases with a positive family history and 368 controls. We examined the frequency of Ala794Gly in an extensive series of familial (n = 910) and unselected (n = 884) breast cancer cases and controls (n = 906), with a high power to detect the suggested breast cancer risk. We also tested if the variant is associated with histopathologic features of breast tumors.Screening of NuMA resulted in identification of 11 exonic variants and 12 variants in introns or untranslated regions. Five missense variants that were further screened in breast cancer cases with a positive family history and controls, were each carried on a unique haplotype. None of the variants, or the haplotypes represented by them, was associated with breast cancer risk although due to low power in this analysis, very low risk alleles may go unrecognized. The NuMA Ala794Gly showed no difference in frequency in the unselected breast cancer case series or familial case series compared to control cases. Furthermore, Ala794Gly did not show any significant association with histopathologic characteristics of the tumors, though Ala794Gly was slightly more frequent among unselected cases with lymph node involvement.Our results do not support the role of NuMA variants as breast cancer susceptibility alleles.Recently, a genome-wide association study with over 25 000 single-nucleotide polymorphisms (SNP) was conducted to discover variants associated with increased breast cancer risk [1]. The initial sample set comprised of 254 German breast cancer cases and 268 controls [1]. Fifty-two SNPs were selected for replication genotyping in two independent sample series, one German (188 cases, 150 controls) and one Austra
Virulence factors and antibiotic susceptibility in enterococci isolated from oral mucosal and deep infections
Gunnar Dahlén,Susanne Blomqvist,Annica Almst?hl,Anette Carlén
Journal of Oral Microbiology , 2012, DOI: 10.3402/jom.v4i0.10855
Abstract: This study evaluates the presence of virulence factors and antibiotic susceptibility among enterococcal isolates from oral mucosal and deep infections. Forty-three enterococcal strains from oral mucosal lesions and 18 from deep infections were isolated from 830 samples that were sent during 2 years to Oral Microbiology, University of Gothenburg, for analysis. The 61 strains were identified by 16S rDNA, and characterized by the presence of the virulence genes efa A (endocarditis gene), gel E (gelatinase gene), ace (collagen binding antigen gene), asa (aggregation substance gene), cyl A (cytolysin activator gene) and esp (surface adhesin gene), tested for the production of bacteriocins and presence of plasmids. MIC determination was performed using the E-test method against the most commonly used antibiotics in dentistry, for example, penicillin V, amoxicillin and clindamycin. Vancomycin was included in order to detect vancomycin-resistant enterococci (VRE) strains. Sixty strains were identified as Enterococcus faecalis and one as Enterococcus faecium. All the virulence genes were detected in more than 93.3% (efa A and esp) of the E. faecalis strains, while the presence of phenotypic characteristics was much lower (gelatinase 10% and hemolysin 16.7%). Forty-six strains produced bacteriocins and one to six plasmids were detected in half of the isolates. Enterococcal strains from oral infections had a high virulence capacity, showed bacteriocin production and had numerous plasmids. They were generally susceptible to ampicillins but were resistant to clindamycin, commonly used in dentistry, and no VRE-strain was found.
Effect of image compression and scaling on automated scoring of immunohistochemical stainings and segmentation of tumor epithelium
Juho Konsti, Mikael Lundin, Nina Linder, Caj Haglund, Carl Blomqvist, Heli Nevanlinna, Kirsimari Aaltonen, Stig Nordling, Johan Lundin
Diagnostic Pathology , 2012, DOI: 10.1186/1746-1596-7-29
Abstract: Two tissue microarray (TMA) slides containing 800 samples of breast cancer tissue immunostained against Ki-67 protein and two TMA slides containing 144 samples of colorectal cancer immunostained against EGFR were digitized with a whole-slide scanner. The TMA images were JPEG2000 wavelet compressed with four compression ratios: lossless, and 1:12, 1:25 and 1:50 lossy compression. Each of the compressed breast cancer images was furthermore scaled down either to 1:1, 1:2, 1:4, 1:8, 1:16, 1:32, 1:64 or 1:128. Breast cancer images were analyzed using an algorithm that quantitates the extent of staining in Ki-67 immunostained images, and EGFR immunostained colorectal cancer images were analyzed with an automated tumor segmentation algorithm. The automated tools were validated by comparing the results from losslessly compressed and non-scaled images with results from conventional visual assessments. Percentage agreement and kappa statistics were calculated between results from compressed and scaled images and results from lossless and non-scaled images.Both of the studied image analysis methods showed good agreement between visual and automated results. In the automated IHC quantification, an agreement of over 98% and a kappa value of over 0.96 was observed between losslessly compressed and non-scaled images and combined compression ratios up to 1:50 and scaling down to 1:8. In automated tumor segmentation, an agreement of over 97% and a kappa value of over 0.93 was observed between losslessly compressed images and compression ratios up to 1:25.The results of this study suggest that images stored for assessment of the extent of immunohistochemical staining can be compressed and scaled significantly, and images of tumors to be segmented can be compressed without compromising computer-assisted analysis results using studied methods.The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2442925476534995 webciteComputer-assisted
Long-term survival of women with basal-like ductal carcinoma in situ of the breast: a population-based cohort study
Wenjing Zhou, Karin Jirstr?m, Christine Johansson, Rose-Marie Amini, Carl Blomqvist, Olorunsola Agbaje, Fredrik W?rnberg
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-653
Abstract: All 458 women with a primary DCIS diagnosed between 1986 and 2004, in Uppland and V?stmanland, Sweden were included. TMA blocks were constructed. To classify the DCIS tumors, we used immunohistochemical (IHC) markers (estrogen-, progesterone-, HER2, cytokeratin 5/6 and epidermal growth factor receptor) as a surrogate for the gene expression profiling. The association with prognosis was examined for basal-like DCIS and other subtypes using Kaplan-Meier survival analyses and Cox proportional hazards regression models.IHC data were complete for 392 women. Thirty-two were basal-like (8.2%), 351 were luminal or HER2-positive (89.5%) and 9 unclassified (2.3%). Seventy-six women had a local recurrence of which 34 were invasive. Another 3 women had general metastases as first event. Basal-like DCIS showed a higher risk of local recurrence and invasive recurrence 1.8 (Confidence interval (CI) 95%, 0.8-4.2) and 1.9 (0.7-5.1), respectively. However, the difference was not statistically significant. Also, no statistically significant increased risk was seen for triple-negative or high grade DCIS.Basal-like DCIS showed about a doubled, however not statistically significant risk for local recurrence and developing invasive cancer compared with the other molecular subtypes. Molecular subtyping was a better prognostic parameter than histopathological grade.Increased use of screening mammography, beginning in the early 1980 s, has resulted in a dramatic increase in detection of ductal carcinoma in situ (DCIS). DCIS is a pre-invasive disease with a clinically and molecularly heterogeneous presentation that poses a major challenge in both diagnosis and treatment [1-3]. A clinically accepted classification system predicting prognosis is still missing.Recently, the idea of using molecular subtyping to predict the prognosis of invasive breast cancer has been widely accepted [4-8]. The introduction of high-throughput DNA microarray technologies marked an entirely new era of genome-wide ap
Multicellular Tumour Spheroid as a model for evaluation of [18F]FDG as biomarker for breast cancer treatment monitoring
Azita Monazzam, Pasha Razifar, Martin Simonsson, Fredrik Qvarnstr?m, Raymond Josephsson, Carl Blomqvist, Bengt L?ngstr?m, Mats Bergstr?m
Cancer Cell International , 2006, DOI: 10.1186/1475-2867-6-6
Abstract: The response to each anticancer treatment was evaluated by measurement of the [18F]FDG uptake and viable volume of the MTSs after 2 and 3 days of treatment.The effect of Paclitaxel and Docetaxel on [18F]FDG uptake per viable volume was more evident in BT474 (up to 55% decrease) than in MCF-7 (up to 25% decrease).Doxorubicin reduced the [18F]FDG uptake per viable volume more noticeable in MCF-7 (25%) than in BT474 MTSs.Tamoxifen reduced the [18F]FDG uptake per viable volume only in MCF-7 at the highest dose of 1 μM.No effect of Imatinib was observed.MTS was shown to be appropriate to investigate the potential of FDG-PET for early breast cancer treatment monitoring; the treatment effect can be observed before any tumour size changes occur.The combination of PET radiotracers and image analysis in MTS provides a good model to evaluate the relationship between tumour volume and the uptake of metabolic tracer before and after chemotherapy. This feature could be used for screening and selecting PET-tracers for early assessment of treatment response.In addition, this new method gives a possibility to assess quickly, and in vitro, a good preclinical profile of existing and newly developed anti-cancer drugs.Positron emission tomography (PET) is a multi-purpose non-invasive imaging technique with a wide range of applications both in vivo and in vitro [1]. In clinical oncology PET has been used for diagnosis, staging, and restaging after treatment or recurrence of different malignancies, including breast cancer [2-4].PET with 2-fluorine-18-fluoro-2-deoxy-D-glucose ([18F]FDG-PET) represents a functional imaging modality that is based on metabolic characteristics of malignant tumours [5]. The uptake of [18F]FDG into tissue reflects both transport and phosphorylation of glucose by viable cells. Quantitative assessment of tumour metabolism by [18F]FDG-PET represents a novel approach in screening the response of malignant tumours to chemotherapy [6-12].Early assessment of response w
Mast cells and eosinophils in invasive breast carcinoma
Rose-Marie Amini, Kirsimari Aaltonen, Heli Nevanlinna, Ricardo Carvalho, Laura Salonen, P?ivi Heikkil?, Carl Blomqvist
BMC Cancer , 2007, DOI: 10.1186/1471-2407-7-165
Abstract: Tissue microarrays containing 234 cases of invasive breast cancer were prepared and analysed for the presence of stromal mast cells and eosinophils. Tumour infiltrating eosinophils were counted on hematoxylin-eosin slides. Immunostaining for tryptase was done and the total number of mast cells were counted and correlated to the proliferation marker Ki 67, positivity for estrogen and progesterone receptors, clinical parameters and clinical outcome.Stromal mast cells were found to correlate to low grade tumours and estrogen receptor positivity. There was a total lack of eosinophils in breast cancer tumours.A high number of mast cells in the tumours correlated to low-grade tumours and estrogen receptor positivity. Eosinophils are not tumour infiltrating in breast cancers.The stroma surrounding the malignant cells is important for the growth and spread of the malignant tumour. Recently, accumulating evidence suggests that the local inflammatory process, previously believed to be the host response against cancer, might actually contribute to the development of malignancy and the inflammatory response in the tumours has gained increased attention [1-4]. In follicular lymphomas, gene expression analyses have shown that genes associated with infiltrating inflammatory cells are more important than the tumour cells themselves for predicting outcome [5].Tumour-associated eosinophilia has been observed in human cancers, sometimes with different results regarding their association with clinical outcome [6-11].Mast cells derive from a specific bone marrow progenitor cell and migrate into tissues where they mature depending on the microenvironmental conditions.Mast cells may promote tumour development through many different ways. Mast cells could facilitate tumour angiogenesis through heparin-like molecules and heparin could further permit neovascularisation and metastases through its anti-clotting effects [12]. Moreover, mast cells secrete histamine and growth factors, such as VE
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