A kollagén XVII-felülreguláció, malignus transzformáció és tumorprogresszió kapcsolata melanomákban = Correlations between collagen XVII upregulation malignant transformation and tumor-progression in melanomas

A jó- és rosszindulatú melanocytás daganatok elkülöníthetése alapvető fontosságú. Elsőként figyeltük meg, hogy a karcinogenezisben is előforduló matrix-kötő kollagén XVII fehérje, aktivált melanocytákban és melanomákban is kimutatható. A pozitív reakció a sejthez kötött, aa507-529 régióra korlátozódik a matrix-kötő domén hiányzik. A reziduális domén primer és áttéti melanomákban, melanoma sejtvonalakban és atípusos dysplasticus naevus szigetekben termelődött, jóindulatú naevusokban nem. A kollagén XVII ligandjai a laminin-5 és kollagén IV is hiányoztak melanomákból. A kollagén XVII immunreakció átfedő profilt adott az S100, MelanA és HMB45 reakciókkal, de pozitív volt orsósejtes melanomában is. A kollagén XVII kifejeződés statisztikai összefüggött a melanoma proliferációval (emelkedett Ki67, ciklinD1 ill. eltűnő p16ink4 szintek), a daganatok vertikális növekedésével, a Breslow, ill. Clark szerinti terjedésével és az invazív dagantfronttal. A HT199 melanoma sejtvonal xenograftok szintén konstitutíven kifejezték a kollagén XVII fehérjét primer és áttéti lokalizációkban és keringő daganatsejtekben, az invazív sejtek emelkedett fehérjetermelésével. Az aa507-529 regiót célzó kollagén XVII immunterápia a melanoma proliferáció gátlása mellett fokozta az apoptózist és a sejtadhéziót. Összegezve, a kollagén XVII fehérje kifejeződése alkalmas a jó- és a rosszindulatú melanocytás léziók elkülönítésére, valamint az invazív fenotípus és antitest indukálta melanoma sejthalál közvetítésére. | Markers for differentiating malignant from benign melanocytic lesions are essential in melanoma diagnostics. We found collagen XVII, a matrix anchoring transmembrane protein which is upregulated in carcinogenesis, in activated melanocytes and malignant melanomas. The cell residual aa507-529 region but not the matrix-anchoring shedding ectodomain of collagen XVII was detected in primary and metastatic melanomas, melanoma cell lines and in atypical nests of dysplastic nevi, while melanocytic nevi were negative. The natural ligands of collagen XVII, laminin-5 and collagen IV were also missing from most melanomas. Collagen XVII immunoreaction stained spindle cell melanomas and showed partly overlapping profiles with those of S100, Melan-A and HMB45. Collagen XVII expression was statistically associated with melanoma proliferation (elevated Ki67 and cyclin D1 fractions and loss of p16ink4), Breslow thickness, Clark levels, vertical growth phase and invasive tumor fronts. Xenografts of HT199 melanoma cell line constitutively expressed collagen XVII in primary, metastatic and circulating tumor cells, and displayed elevated levels in invasive versus adherent cells in culture. Antibody targeting the aa507-529 region of collagen XVII promoted apoptosis and cell adhesion, while inhibiting proliferation of HT199 cells. Accordingly, collagen XVII protein expression can differentiate melanomas from benign nevi and mediate invasion and antibody induced death of melanoma cells

A myofibroblastok szerepe a vastagbél gyulladásos és daganatos folyamataiban = Role of myofibroblast in inflammatory bowel disease and tumor genesis

A vastagbél stromasejtjeinek és az azokat körülvevő mikrokörnyezetnek elsődleges szerepe van a gyulladásos folyamatok szabályozásában, a tumorok kialakításában és az áttétek képzésében. A gyulladásos folyamatokban és az azt követő szöveti regenerációban alapvető jelentőségűek a myofibroblastok, amelyek által termelt molekulák hatnak az immunrendszer sejtjeire és a hámsejtek proliferációjára. A daganatok myofibroblastokat aktiválhatnak, amelyek fokozott és megváltozott regulátoros ligand (citokin, kemokin, kemotaktikus és növekedési faktorok) termelése őssejt-aktiváción keresztül a hámsejtek kontrollálatlan szaporodásához vezethet. Dolgozatunkban a myofibroblastokkal kapcsolatos tudnivalókat foglaljuk össze, és ismertetjük szerepüket a gyulladásos és a neoplasztikus folyamatokban. | Stroma cells with the microenvironment around them have primary role in the regulation of inflammation processes, conformation of tumors and development of metastasis. Myofibroblasts have essential role in inflammation processes and in the regeneration of encompassed tissue. Molecules produced by them operate the cells of the immunsystem and effect the proliferation of epithelium. Tumors can activate myofibroblasts which can lead to uncontrolled epithelium proliferation across production of changed and increased regulation ligands (such as cytokin, chemokin, chemotactic and other growth factors) and activation of stem cell. This process could lead piling of uncontrolled epithelial cells and can impact later on comformation of tumors. In this study we present an overview about of myofibroblasts and their roles in inflammation and neoplastic processes

Az emlőrák patológiai diagnosztikája, feldolgozása és kórszövettani leletezése. Szakmai útmutatás a III. Emlőrák Konszenzus Konferencia alapján

There have been relevant changes in the diagnosis and treatment of breast cancer to implement the updating of the 2010 recommendations made during the 2nd national consensus conference on the disease. Following a wide interdisciplinary consultation, the present recommendations have been finalized after their public discussion at the 3rd Hungarian Consensus Conference on Breast Cancer. The recommendations cover non-operative and intraoperative diagnostics, the work-up of operative specimens, the determination of prognostic and predictive markers and the content of the cytology and histology reports. Furthermore, it touches some special issues such as the current status of multigene molecular markers, the role of pathologists in clinical trials and prerequisites for their involvement, some relevant points about the future

MEK1 is associated with carboplatin resistance and is a prognostic biomarker in epithelial ovarian cancer

BACKGROUND: Primary systemic treatment for ovarian cancer is surgery, followed by platinum based chemotherapy. Platinum resistant cancers progress/recur in approximately 25% of cases within six months. We aimed to identify clinically useful biomarkers of platinum resistance. METHODS: A database of ovarian cancer transcriptomic datasets including treatment and response information was set up by mining the GEO and TCGA repositories. Receiver operator characteristics (ROC) analysis was performed in R for each gene and these were then ranked using their achieved area under the curve (AUC) values. The most significant candidates were selected and in vitro functionally evaluated in four epithelial ovarian cancer cell lines (SKOV-3-, CAOV-3, ES-2 and OVCAR-3), using gene silencing combined with drug treatment in viability and apoptosis assays. We collected 94 tumor samples and the strongest candidate was validated by IHC and qRT-PCR in these. RESULTS: All together 1,452 eligible patients were identified. Based on the ROC analysis the eight most significant genes were JRK, CNOT8, RTF1, CCT3, NFAT2CIP, MEK1, FUBP1 and CSDE1. Silencing of MEK1, CSDE1, CNOT8 and RTF1, and pharmacological inhibition of MEK1 caused significant sensitization in the cell lines. Of the eight genes, JRK (p = 3.2E-05), MEK1 (p = 0.0078), FUBP1 (p = 0.014) and CNOT8 (p = 0.00022) also correlated to progression free survival. The correlation between the best biomarker candidate MEK1 and survival was validated in two independent cohorts by qRT-PCR (n = 34, HR = 5.8, p = 0.003) and IHC (n = 59, HR = 4.3, p = 0.033). CONCLUSION: We identified MEK1 as a promising prognostic biomarker candidate correlated to response to platinum based chemotherapy in ovarian cancer

Technical note on the validation of a semi-automated image analysis software application for estrogen and progesterone receptor detection in breast cancer

<p>Abstract</p> <p>Background</p> <p>The immunohistochemical detection of estrogen (ER) and progesterone (PR) receptors in breast cancer is routinely used for prognostic and predictive testing. Whole slide digitalization supported by dedicated software tools allows quantization of the image objects (e.g. cell membrane, nuclei) and an unbiased analysis of immunostaining results. Validation studies of image analysis applications for the detection of ER and PR in breast cancer specimens provided strong concordance between the pathologist's manual assessment of slides and scoring performed using different software applications.</p> <p>Methods</p> <p>The effectiveness of two connected semi-automated image analysis software (<it>NuclearQuant </it>v. 1.13 application for <it>Pannoramic</it>™ <it>Viewer </it>v. 1.14) for determination of ER and PR status in formalin-fixed paraffin embedded breast cancer specimens immunostained with the automated Leica Bond Max system was studied. First the detection algorithm was calibrated to the scores provided an independent assessors (pathologist), using selected areas from 38 small digital slides (created from 16 cases) containing a mean number of 195 cells. Each cell was manually marked and scored according to the Allred-system combining frequency and intensity scores. The performance of the calibrated algorithm was tested on 16 cases (14 invasive ductal carcinoma, 2 invasive lobular carcinoma) against the pathologist's manual scoring of digital slides.</p> <p>Results</p> <p>The detection was calibrated to 87 percent object detection agreement and almost perfect Total Score agreement (Cohen's kappa 0.859, quadratic weighted kappa 0.986) from slight or moderate agreement at the start of the study, using the un-calibrated algorithm. The performance of the application was tested against the pathologist's manual scoring of digital slides on 53 regions of interest of 16 ER and PR slides covering all positivity ranges, and the quadratic weighted kappa provided almost perfect agreement (κ = 0.981) among the two scoring schemes.</p> <p>Conclusions</p> <p><it>NuclearQuant </it>v. 1.13 application for <it>Pannoramic</it>™ <it>Viewer </it>v. 1.14 software application proved to be a reliable image analysis tool for pathologists testing ER and PR status in breast cancer.</p

Identification of a claudin-4 and E-cadherin score to predict prognosis in breast cancer

The elevated expression of claudins (CLDN) and E-cadherin (CDH-1) was found to correlate with poor prognostic features. Our aim was to perform a comprehensive analysis to assess their potential to predict prognosis in breast cancer. The expression of CLDN-1, -3-5, -7, -8, -10, -15, -18, and E-cadherin at the mRNA level was evaluated in correlation with survival in datasets containing expression measurements of 1809 breast cancer patients. The breast cancer tissues of 197 patients were evaluated with tissue microarray technique and immunohistochemical method for CLDN-1-5, -7, and E-cadherin protein expression. An additional validation set of 387 patients was used to test the accuracy of the resulting prognostic score. Based on the bioinformatic screening of publicly-available datasets, the metagene of CLDN-3, -4, -7, and E-cadherin was shown to have the most powerful predictive power in the survival analyses. An immunohistochemical protein profile consisting of CLDN-2, -4, and E-cadherin was able to predict outcome in the most effective manner in the training set. Combining the overlapping members of the above two methods resulted in the claudin-4 and E-cadherin score (CURIO), which was able to accurately predict relapse-free survival in the validation cohort (P=0.029). The multivariate analysis, including clinicopathological variables and the CURIO, showed that the latter kept its predictive power (P=0.040). Furthermore, the CURIO was able to further refine prognosis, separating good versus poor prognosis subgroups in luminal A, luminal B, and triple-negative breast cancer intrinsic subtypes. In breast cancer, the CURIO provides additional prognostic information besides the routinely utilized diagnostic approaches and factors. © 2011 Japanese Cancer Association