Unnafected female carriers of
and
pathogenic/likely pathogenic variants (P/LPVs) are at higher risk of breast cancer (BC) and ovarian cancer (OC). In the retrospective single-institution study in the ...Czech Republic, we analyzed the rate, longitudinal trends, and effectiveness of prophylactic risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) on the incidence of BC and OC in
/
carriers diagnosed between years (y) 2000 to 2020. The study included 496 healthy female
/
carriers. The median follow-up was 6.0 years. RRM was performed in 156 (31.5%, mean age 39.3 y, range 22-61 y) and RRSO in 234 (47.2%, mean age 43.2 y, range 28-64 y)
/
carriers. A statistically significant increase of RRM (from 12% to 29%) and RRSO (from 31% to 42%) was observed when comparing periods 2005-2012 and 2013-2020 (
< 0.001). BC developed in 15.9% of
carriers without RRM vs. 0.6% of
carriers after RRM (HR 20.18, 95% CI 2.78- 146.02;
< 0.001). OC was diagnosed in 4.3% vs. 0% of
carriers without vs. after RRSO (HR not defined due to 0% occurrence in the RRSO group,
< 0.001). Study results demonstrate a significant increase in the rate of prophylactic surgeries in
healthy carriers after 2013 and the effectiveness of RRM and RRSO on the incidence of BC and OC in these populations.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Raman optical activity (ROA) is inherently sensitive to the secondary structure of biomolecules, which makes it a method of interest for finding new approaches to clinical applications based on blood ...plasma analysis, for instance the diagnostics of several protein-misfolding diseases. Unfortunately, real blood plasma exhibits strong background fluorescence when excited at 532 nm; hence, measuring the ROA spectra appears to be impossible. Therefore, we established a suitable method using a combination of kinetic quenchers, filtering, photobleaching, and a mathematical correction of residual fluorescence. Our method reduced the background fluorescence approximately by 90 %, which allowed speedup for each measurement by an average of 50 %. In addition, the signal-to-noise ratio was significantly increased, while the baseline distortion remained low. We assume that our method is suitable for the investigation of human blood plasma by ROA and may lead to the development of a new tool for clinical diagnostics.
Graphical abstract
The effect of a newly developed fluorescence quenching method for the ROA measurements of human blood plasma
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Colorectal cancer is one of the most common and often fatal cancers in humans, but it has the highest chance of a cure if detected at an early precancerous stage. Carcinogenesis in the colon begins ...as an uncontrolled growth forming polyps. Some of these polyps can finally be converted to colon cancer. Early diagnosis of adenomatous polyps is the main approach for screening and preventing colorectal cancer, and vibration spectroscopy can be used for this purpose. This work is focused on evaluating FTIR and Raman spectroscopy as a tool in the ex vivo analysis of colorectal polyps, which could be important for the early diagnosis of colorectal carcinoma. Multivariate analyses (PCA and LDA) were used to assist the spectroscopic discrimination of normal colon tissue, as well as benign and malignant colon polyps. The spectra demonstrated evident differences in the characteristic bands of the main tissue constituents, i.e., proteins, nucleic acids, lipids, polysaccharides, etc. Suitable models for discriminating the three mentioned diagnostic groups were proposed based on multivariate analyses of the spectroscopic data. LDA classification was especially successful in the case of a combined set of 55 variables from the FTIR, FT Raman and dispersion Raman spectra. This model can be proposed for ex vivo colorectal cancer diagnostics in combination with the colonoscopic extraction of colon polyps for further testing. This pilot study is a precursor for the further evaluation of the diagnostic potential for the simultaneous in vivo application of colonoscopic Raman probes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Chiroptical methods are widely used in structural and conformational analyses of biopolymers. The application of these methods to investigations of biofluids would provide new avenues for the ...molecular diagnosis of protein-misfolding diseases. In this work, samples of human blood plasma and hen egg white were analyzed using a combination of conventional and chiroptical methods: ultraviolet absorption/electronic circular dichroism (UV/ECD), Fourier transform infrared absorption/vibrational circular dichroism (FTIR/VCD), and Raman scattering/Raman optical activity (Raman/ROA). For comparison, the main components of these substances—human serum albumin (HSA) and ovalbumin (Ova)—were also analyzed by these methods. The ultraviolet region of the ECD spectrum was analyzed using the CDNN CD software package to evaluate the secondary structures of the proteins. The UV/ECD, FTIR/VCD, and Raman/ROA spectra of the substances were quite similar to those of the corresponding major proteins, while some differences were also detected and explained. The conclusions drawn from the FTIR/VCD and Raman/ROA data were in good agreement with the secondary structures calculated from ECD. The results obtained in this work demonstrate that the chiroptical methods used here can be applied to analyze not only pure protein solutions but also more complex systems, such as biological fluids.
Figure
Analysis of human blood plasma and hen egg white by ECD, VCD and ROA.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Colorectal cancer is one of the most abundant causes of cancer deaths in the world. At an early stage, the established clinical procedures have low reliability and sensitivity. Therefore, we tested a ...novel approach based on chiroptical methods such as electronic circular dichroism (ECD) and Raman optical activity (ROA). These methods are suitable for detecting slight changes in the 3D structure of chiral biomolecules, some of which may be caused by pathological processes occurring during cancer growth. Fifty-five blood plasma samples were analyzed using the combination of ECD and ROA supplemented by conventional Raman and FT-IR spectroscopy. All obtained spectra were evaluated together by linear discriminant analysis. The accuracy of sample discrimination reached 100% and the subsequent leave-one-out cross-validation resulted in 93% sensitivity and 81% specificity. The achieved results indicate that chiroptical methods supplemented by Raman and FT-IR spectroscopy might be new supporting and minimally invasive tools in the clinical diagnosis of colon cancer.
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•Raman spectroscopy and ROA allowed the differentiation of gastrointestinal cancers.•Achieved classification accuracy is relevant to clinical practice.•Most of the identified spectral ...markers were assigned to proteins.•Carotenoids are indicators of overall health status rather than disease biomarkers.
Improving the early diagnosis of gastrointestinal cancers is a crucial step in reducing their mortality. Given the non-specificity of the initial symptoms, the ability of any diagnostic method to differentiate between various types of gastrointestinal cancers also needs to be addressed. To detect disease-specific alterations in biomolecular structure and composition of the blood plasma, we have implemented an approach combining Raman spectroscopy and its conformation-sensitive polarized version, Raman optical activity, to analyze blood plasma samples of patients suffering from three different types of gastrointestinal cancer – hepatocellular, colorectal and pancreatic. First, we aimed to discriminate any type of gastrointestinal cancer from healthy control individuals; inthenext step, the focus was on differentiating among the three cancer types studied. The more straightforward of the two statistical approaches tested, the combination of linear discriminant analysis and principal component analysis applied to the entire spectral dataset, allowed the discrimination of cancer and control samples with 87% accuracy. The three gastrointestinal cancers were classified with an overall accuracy of 76%. The second method, the linear discriminant analysis applied to a selection of spectral bands, yielded even higher values. Cancer and control samples were distinguished with 89% accuracy and hepatocellular, colorectal and pancreatic cancer with an overall accuracy of 87%. The results obtained in our study suggest that the proposed approach may become a disease-specific diagnostic tool in daily clinical practice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Women with BRCA 1/2 pathogenic/likely pathogenic variants (P/LPVs) have a high lifetime risk of developing breast and ovarian cancer. The aim of the retrospective study is to analyze the rate, ...longitudinal trends, and effectiveness of prophylactic risk-reducing mastectomy (RRM) and salpingo-oophorectomy (RRSO) on the incidence of breast and ovarian cancer. We analyzed data from 496 unaffected BRCA1/2 carriers with a median follow-up of 6.0 years. A statistically significant increase of RRM (12% vs. 29%) and RRSO (31% vs. 42%) was observed when comparing periods 2005-2012 and 2013-2020 (p < 0.001). BC developed in 15.9% of BRCA1/2 carriers without RRM vs. 0.6% of BRCA1/2 carriers after RRM (HR 20.18, p < 0.001). OC was diagnosed in 4.3% vs. 0% of BRCA1/2 carriers without vs. after RRSO (p < 0.001). Data shows a high effectiveness and significant increase of prophylactic surgeries over 20 years period in a central European population of BRCA1/2 carriers. Unnafected female carriers of BRCA1 and BRCA2 pathogenic/likely pathogenic variants (P/LPVs) are at higher risk of breast cancer (BC) and ovarian cancer (OC). In the retrospective single-institution study in the Czech Republic, we analyzed the rate, longitudinal trends, and effectiveness of prophylactic risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) on the incidence of BC and OC in BRCA1/2 carriers diagnosed between years (y) 2000 to 2020. The study included 496 healthy female BRCA1/2 carriers. The median follow-up was 6.0 years. RRM was performed in 156 (31.5%, mean age 39.3 y, range 22-61 y) and RRSO in 234 (47.2%, mean age 43.2 y, range 28-64 y) BRCA1/2 carriers. A statistically significant increase of RRM (from 12% to 29%) and RRSO (from 31% to 42%) was observed when comparing periods 2005-2012 and 2013-2020 (p < 0.001). BC developed in 15.9% of BRCA1/2 carriers without RRM vs. 0.6% of BRCA1/2 carriers after RRM (HR 20.18, 95% CI 2.78- 146.02; p < 0.001). OC was diagnosed in 4.3% vs. 0% of BRCA1/2 carriers without vs. after RRSO (HR not defined due to 0% occurrence in the RRSO group, p < 0.001). Study results demonstrate a significant increase in the rate of prophylactic surgeries in BRCA1/2 healthy carriers after 2013 and the effectiveness of RRM and RRSO on the incidence of BC and OC in these populations.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Defects in the immune response correlated with poor prognosis and therefore in recent years, research focused on a precise description of the status and function of the immune system and its ...possible effect in cancer patients.
Although more than 2/3 of treated patients respond to the endocrine therapy, most patients with metastatic breast cancer will develop resistance.. It appears that other factor contributing to the resistance may be a transforming factor-beta (TGF-beta). It is highly immunosuppressive factor that inhibits the natural and specific immunity against tumors and stimulates production of vascular endothelial growth factor /VEGF.
The purpose of the study was to monitor immune responses in patients with hormone receptor positive breast cancer resistant to hormone therapy, particularly the examination of cellular (CD4, CD8, HLA-DR) as well as humoral immunity. TGF beta, and VEGF production was monitored and we analyzed the changes during hormonal treatment.
Methods: 85 patients included in the research project were implemented routine cancer treatment with endocrine therapy. Basic parameters (histological type and grade, the degree of expression of ER and PR, HER2, and the proliferative marker) were established. Patients were evaluated by a cancer clinical immunologist to exclude immune disorders, allergic or autoimmune origin. TGF beta, VEGF were measured by ELISA and anti-tumor cellular immunity (CD4, CD8, antigen presenting cells ) were measured by flow cytometry.
Results In patients with resistance to endocrine therapy mainly depression in cellular immunity was found. Immunglobulin plasma level was decreased as well (mainly IgG4 subtype). Most patients have shown clinical symptoms of immunodeficiency (frequent infections of respiratory or urinary tract, herpetic infections) TGF beta as well as VEGF plasma level were increased. Significant increase of autoantibodies production was found, particularly in those, involved into blood coagulation process/anti phospholipide and anti cardiolipin autoantibodies.
Conclusion Correlation of these factors with resistance to hormonal therapy, and the state of anticancer immunity could help in the future with the prediction of resistance to hormonal therapy and contribute to the selection of targeted immune therapy in cancer patients.
Dedication: This project was supported by grant IGA NT11168-3/2010.
Citation Format: Eva Zavadova, Bohuslav Konopasek, Michal Vocka, Michaela Miskovicova, Jan Spacek, Terezie Fucikova, Lubos Petruzelka. Abnormalities in cellular and humoral immunity in breast cancer patients resistant to endocrine therapy. abstract. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B9.
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