| 1. |
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| 2. |
- Brunnström, Hans, et al.
(författare)
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Interventional and EBUS cytology in Sweden
- 2022
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Ingår i: Seminars in Diagnostic Pathology. - : Elsevier BV. - 0740-2570. ; 39:6, s. 458-462
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Forskningsöversikt (refereegranskat)abstract
- Interventional cytology was first introduced in Sweden in the late 1940ies by Sixten Franzén at the Karolinska University Hospital in Solna, Stockholm. In the early 1950ies, Nils Söderström started using the technique at the University Hospital in Lund. Cytology was successively established as common practice at the pathology departments in Sweden, and e.g. Solna and Lund today have a high rate of cytological samples. Over the years new techniques, such as endobronchial ultrasound (EBUS)-guided fine-needle aspirations, and analyses have been introduced, contributing to the maintained value of cytology as a diagnostic method. In this article, we present a brief history and the current situation of cytology in Sweden with focus on interventional and EBUS cytology.
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| 3. |
- Darai-Ramqvist, Eva, et al.
(författare)
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Array-CGH and multipoint FISH to decode complex chromosomal rearrangements
- 2006
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 7, s. 330-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recently, several high-resolution methods of chromosome analysis have been developed. It is important to compare these methods and to select reliable combinations of techniques to analyze complex chromosomal rearrangements in tumours. In this study we have compared array-CGH (comparative genomic hybridization) and multipoint FISH (mpFISH) for their ability to characterize complex rearrangements on human chromosome 3 (chr3) in tumour cell lines. We have used 179 BAC/PAC clones covering chr3 with an approximately 1 Mb resolution to analyze nine carcinoma lines. Chr3 was chosen for analysis, because of its frequent rearrangements in human solid tumours. Results: The ploidy of the tumour cell lines ranged from near-diploid to near-pentaploid. Chr3 locus copy number was assessed by interphase and metaphase mpFISH. Totally 53 chr3 fragments were identified having copy numbers from 0 to 14. MpFISH results from the BAC/PAC clones and array-CGH gave mainly corresponding results. Each copy number change on the array profile could be related to a specific chromosome aberration detected by metaphase mpFISH. The analysis of the correlation between real copy number from mpFISH and the average normalized inter-locus fluorescence ratio (ANILFR) value detected by array-CGH demonstrated that copy number is a linear function of parameters that include the variable, ANILFR, and two constants, ploidy and background normalized fluorescence ratio. Conclusion: In most cases, the changes in copy number seen on array-CGH profiles reflected cumulative chromosome rearrangements. Most of them stemmed from unbalanced translocations. Although our chr3 BAC/PAC array could identify single copy number changes even in pentaploid cells, mpFISH provided a more accurate analysis in the dissection of complex karyotypes at high ploidy levels.
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| 4. |
- Darai-Ramqvist, Eva
(författare)
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Involvement of evolutionarily plastic regions in cancer associated CHR3 aberrations
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A functional test to identify tumor antagonizing regions on chromosome 3 (chr3), called the Elimination Test, was developed in our group. It is based on microcell mediated transfer of human chr3 into mouse or human tumor cells and analysis of the monochromosomal hybrids after their growth in vivo. We identified three regions on 3p14-p22, which were frequently lost in derived tumors (common or frequently eliminated regions). In order to understand the role of these regions in tumor development, we continued the study following two leads: analysis of breakpoint clusters to identify and characterize possible instability features and search for tumor suppressor genes within the deleted regions. First, we identified and characterized a common eliminated region 1 (CER1) homologous sequence in mouse, where it was divided into two syntenic blocks on chromosome 9. In these blocks, the gene order and content was maintained with exception of two mouse gene duplications. Comparative analysis helped us to characterize five previously not identified mouse genes (Kiss et al. 2002). A more extensive comparative study of CER1 showed that its border regions are characterized by evolutionary plasticity: synteny breaks in several species, recent tandem gene duplications, retroposed pseudogene insertions, and horizontal evolution of the genes. Thus we showed that the cancer associated breakpoint regions have features of evolutionary plasticity. These results and other publications from our group suggested structural instability at the borders of eliminated regions identified by the Elimination Test (Darai et al. 2005) (Kost-Alimova et al. 2003; Kost-Alimova et al. 2004). As a next step, in order to analyze rearrangements of entire chr3 in human tumor cells, we developed and compared two high resolution methods, array-CGH and mpFISH. We proved that although our 1Mb chr3 BAC/PAC array could identify single copy number changes even in pentaploid cells, mpFISH provided a more accurate analysis in the dissection of complex karyotypes at high ploidy levels. In heterogeneous or normal cell contaminated samples the most precise analysis can be made by mpFISH due to its ability to give information at single cell level (Darai-Ramqvist et al. 2006). Using high resolution methods we analyzed ten carcinoma cell lines and identified two new hot spots of tumor breakpoints at 3p12-p13 and 3q21. These tumor breakpoint regions carried large segmental duplications, retrotransposable elements and satellite repeats, which participated in recent primate evolution and, as we suggest, are associated with structural chromosomal instability (CIN). CIN is an ongoing dynamic process. Therefore in order to prove that the instability at the breakpoint regions characterizes structural CIN phenotype and it is required for tumor development and progression, dynamic analysis of the tumors must be done. This may elucidate the mechanism of tumor development; and may help to develop CIN phenotype markers useful in choice of consequent treatment. Following the second lead of our study, we have analyzed a putative tumor suppressor gene LIMD1, which is located within the deleted central part of CER1. We found that it binds specifically to pRb and suppresses E2F driven transcription. A tumor suppressor effect of this gene was proven in in vitro and in vivo experiments, as well as in tumor biopsies (Sharp et al. 2004). In another part of the study we analyzed in details chr3 rearrangements in human renal cell carcinoma and nasopharyngeal carcinoma derived monochromosomal (chr3) hybrids and showed that aneuploid tumors maintain a mandatory chromosomal segment balance with stringency concerning no gain of 3p14-21 and no loss of 3q26-27. We concluded that the mechanism of tumor suppression by chr3 transfer is based on the alternative quantitative model. According to this model the tumor cell does not tolerate an increased dosage of the relevant gene or segment, and the lost part can be either of normal cell derived exogeneous or tumor derived endogenous origin (Kost-Alimova et al. 2007). First, we identified and characterized a common eliminated region 1 (CER1) homologous sequence in mouse, where it was divided into two syntenic blocks on chromosome 9. In these blocks, the gene order and content was maintained with exception of two mouse gene duplications. Comparative analysis helped us to characterize five previously not identified mouse genes (Kiss et al. 2002). A more extensive comparative study of CER1 showed that its border regions are characterized by evolutionary plasticity: synteny breaks in several species, recent tandem gene duplications, retroposed pseudogene insertions, and horizontal evolution of the genes. Thus we showed that the cancer associated breakpoint regions have features of evolutionary plasticity. These results and other publications from our group suggested structural instability at the borders of eliminated regions identified by the Elimination Test (Darai et al. 2005) (Kost-Alimova et al. 2003; Kost-Alimova et al. 2004). As a next step, in order to analyze rearrangements of entire chr3 in human tumor cells, we developed and compared two high resolution methods, array-CGH and mpFISH. We proved that although our 1Mb chr3 BAC/PAC array could identify single copy number changes even in pentaploid cells, mpFISH provided a more accurate analysis in the dissection of complex karyotypes at high ploidy levels. In heterogeneous or normal cell contaminated samples the most precise analysis can be made by mpFISH due to its ability to give information at single cell level (Darai-Ramqvist et al. 2006). Using high resolution methods we analyzed ten carcinoma cell lines and identified two new hot spots of tumor breakpoints at 3p12-p13 and 3q21. These tumor breakpoint regions carried large segmental duplications, retrotransposable elements and satellite repeats, which participated in recent primate evolution and, as we suggest, are associated with structural chromosomal instability (CIN). CIN is an ongoing dynamic process. Therefore in order to prove that the instability at the breakpoint regions characterizes structural CIN phenotype and it is required for tumor development and progression, dynamic analysis of the tumors must be done. This may elucidate the mechanism of tumor development; and may help to develop CIN phenotype markers useful in choice of consequent treatment. Following the second lead of our study, we have analyzed a putative tumor suppressor gene LIMD1, which is located within the deleted central part of CER1. We found that it binds specifically to pRb and suppresses E2F driven transcription. A tumor suppressor effect of this gene was proven in in vitro and in vivo experiments, as well as in tumor biopsies (Sharp et al. 2004). In another part of the study we analyzed in details chr3 rearrangements in human renal cell carcinoma and nasopharyngeal carcinoma derived monochromosomal (chr3) hybrids and showed that aneuploid tumors maintain a mandatory chromosomal segment balance with stringency concerning no gain of 3p14-21 and no loss of 3q26-27. We concluded that the mechanism of tumor suppression by chr3 transfer is based on the alternative quantitative model. According to this model the tumor cell does not tolerate an increased dosage of the relevant gene or segment, and the lost part can be either of normal cell derived exogeneous or tumor derived endogenous origin (Kost-Alimova et al. 2007).
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| 5. |
- Darai-Ramqvist, Eva, et al.
(författare)
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Microenvironment-dependent phenotypic changes in a SCID mouse model for malignant mesothelioma
- 2013
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Malignant mesothelioma is an aggressive, therapy-resistant tumor. Mesothelioma cells may assume an epithelioid or a sarcomatoid phenotype, and presence of sarcomatoid cells predicts poor prognosis. In this study, we investigated differentiation of mesothelioma cells in a xenograft model, where mesothelioma cells of both phenotypes were induced to form tumors in severe combined immunodeficiency mice.Methods: Xenografts were established and thoroughly characterized using a comprehensive immunohistochemical panel, array comparative genomic hybridization (aCGH) of chromosome 3, fluorescent in situ hybridization, and electron microscopy.Results: Epithelioid and sarcomatoid cells gave rise to xenografts of similar epithelioid morphology. While sarcomatoid-derived xenografts had higher growth rates, the morphology and expression of differentiation-related markers was similar between xenografts derived from both phenotypes. aCGH showed a convergent genotype for both xenografts, resembling the original aggressive sarcomatoid cell sub-line.Conclusion: Human mesothelioma xenografts from sarcomatoid and epithelioid phenotypes converged to a similar differentiation state, and genetic analyses suggested that clonal selection in the mouse microenvironment was a major contributing factor. This thoroughly characterized animal model can be used for further studies of molecular events underlying tumor cell differentiation.
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| 6. |
- De Bustos, Cecilia, et al.
(författare)
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Analysis of copy number variation in normal human population within a region containing complex segmental duplications on 22q11 using high resolution array-CGH
- 2006
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Ingår i: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 88:2, s. 152-162
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Tidskriftsartikel (refereegranskat)abstract
- A previously detected copy number polymorphism (Ep CNP) in patients affected with neuroectodermal tumors led us to investigate its frequency and length in the normal population. For this purpose, a program called Sequence Allocator was developed and applied for the construction of an array that consisted of unique and duplicated fragments, allowing the assessment of copy number variation within regions of segmental duplications. The average resolution of this array was 11 kb and we determined the size of the Ep CNP to be 290 kb. Analysis of normal controls identified 7.7 and 7.1% gains in peripheral blood and lymphoblastoid cell line (LCL) DNA, respectively, while deletions were found only in the LCL group (7.1%). This array platform allows the detection of DNA copy number variation within regions of pronounced genomic complexity, which constitutes an improvement over available technologies.
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| 7. |
- Koriakina, Nadezhda, 1991-, et al.
(författare)
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Visualization of convolutional neural network class activations in automated oral cancer detection for interpretation of malignancy associated changes
- 2019
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Ingår i: 3rd NEUBIAS Conference, Luxembourg, 2-8 February 2019.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Cancer of the oral cavity is one of the most common malignancies in the world. The incidence of oral cavity and oropharyngeal cancer is increasing among young people. It is noteworthy that the oral cavity can be relatively easily accessed for routine screening tests that could potentially decrease the incidence of oral cancer. Automated deep learning computer aided methods show promising ability for detection of subtle precancerous changes at a very early stage, also when visual examination is less effective. Although the biological nature of these malignancy associated changes is not fully understood, the consistency of morphology and textural changes within a cell dataset could shed light on the premalignant state. In this study, we are aiming to increase understanding of this phenomenon by exploring and visualizing what parts of cell images are considered as most important when trained deep convolutional neural networks (DCNNs) are used to differentiate cytological images into normal and abnormal classes.Materials and methods: Cell samples are collected with a brush at areas of interest in the oral cavity and stained according to standard PAP procedures. Digital images from the slides are acquired with a 0.32 micron pixel size in greyscale format (570 nm bandpass filter). Cell nuclei are manually selected in the images and a small region is cropped around each nucleus resulting in images of 80x80 pixels. Medical knowledge is not used for choosing the cells but they are just randomly selected from the glass; for the learning process we are only providing ground truth on the patient level and not on the cell level. Overall, 10274 images of cell nuclei and the surrounding region are used to train state-of-the-art DCNNs to distinguish between cells from healthy persons and persons with precancerous lesions. Data augmentation through 90 degrees rotations and mirroring is applied to the datasets. Different approaches for class activation mapping and related methods are utilized to determine what image regions and feature maps are responsible for the relevant class differentiation.Results and Discussion:The best performing of the observed deep learning architectures reaches a per cell classification accuracy surpassing 80% on the observed material. Visualizing the class activation maps confirms our expectation that the network is able to learn to focus on specific relevant parts of the sample regions. We compare and evaluate our findings related to detected discriminative regions with the subjective judgements of a trained cytotechnologist. We believe that this effort on improving understanding of decision criteria used by machine and human leads to increased understanding of malignancy associated changes and also improves robustness and reliability of the automated malignancy detection procedure.
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| 8. |
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| 9. |
- Lindquist, Kajsa Ericson, et al.
(författare)
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Real-world diagnostic accuracy and use of immunohistochemical markers in lung cancer diagnostics
- 2021
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Ingår i: Biomolecules. - : MDPI AG. - 2218-273X. ; 11:11
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Accurate and reliable diagnostics are crucial as histopathological type influ-ences selection of treatment in lung cancer. The aim of this study was to evaluate real-world accuracy and use of immunohistochemical (IHC) staining in lung cancer diagnostics. Materials and Methods: The diagnosis and used IHC stains for small specimens with lung cancer on follow-up resection were retrospectively investigated for a 15-month period at two major sites in Sweden. Additionally, 10 pathologists individually suggested diagnostic IHC staining for 15 scanned bronchial and lung biopsies and cytological specimens. Results: In 16 (4.7%) of 338 lung cancer cases, a discordant diagnosis of potential clinical relevance was seen between a small specimen and the fol-low-up resection. In half of the cases, there was a different small specimen from the same investi-gational work-up with a concordant diagnosis. Diagnostic inaccuracy was often related to a squa-mous marker not included in the IHC panel (also seen for the scanned cases), the case being a neu-roendocrine tumor, thyroid transcription factor-1 (TTF-1) expression in squamous cell carcinomas (with clone SPT24), or poor differentiation. IHC was used in about 95% of cases, with a higher number of stains in biopsies and in squamous cell carcinomas and especially neuroendocrine tumors. Pre-surgical transthoracic samples were more often diagnostic than bronchoscopic ones (72–85% vs. 9–53% for prevalent types). Conclusions: Although a high overall diagnostic accuracy of small specimens was seen, small changes in routine practice (such as consequent inclusion of p40 and TTF-1 clone 8G7G3/1 in the IHC panel for non-small cell cancer with unclear morphology) may lead to improvement, while reducing the number of IHC stains would be preferable from a time and cost perspective.
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| 10. |
- Lu, Jiahao, et al.
(författare)
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A Deep Learning based Pipeline for Efficient Oral Cancer Screening on Whole Slide Images
- 2019
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Oral cancer incidence is rapidly increasing worldwide. The most important determinant factor in cancer survival is early diagnosis. To facilitate large scale screening, we propose a fully automated end-to-end pipeline for oral cancer screening on whole slide cytology images. The pipeline consists of regression based nucleus detection, followed by per cell focus selection, and CNN based classification. We demonstrate that the pipeline provides fast and efficient cancer classification of whole slide cytology images, improving over previous results. The complete source code is made available as open source (https://github.com/MIDA-group/OralScreen).
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