1,720,975 research outputs found
VALUTAZIONE DI HER2 NEL CARCINOMA SIEROSO ENDOMETRIALE
No full textBACKGROUND: Uterine serous carcinoma (USC) is an aggressive tumor, responsible for approximately half of endometrial carcinoma-related mortality. A subset of USC shows HER2 overexpression due to ERBB2 amplification, and a recent phase 2 trial demonstrated that these patients benefit from treatment with trastuzumab. Therefore, accurate assessment of HER2 status is critical to properly select patients for targeted therapy. However, previous work has shown a significant intratumoral heterogeneity of ERBB2 amplification in USC and Next Generation Sequencing (NGS) is (and will be) increasingly used in the identification of targetable or clinically relevant (such as POLE point mutations) molecular alterations in endometrial carcinoma.
AIMS: To investigate the potential clinical impact of HER2 heterogeneity by examining HER2 status in paired endometrial biopsies, hysterectomy specimens, and metastatic lesions from patients with USC. To investigate the ability of a targeted NGS panel to detect ERBB2 amplification.
MATERIALS AND METHODS: Cases of USC were retrospectively identified, for which FFPE tumoral tissue was available (biopsy, hysterectomy, and/or metastasis specimen from the same patient). HER2 expression was assessed by immunohistochemistry (IHC) on all samples and scored using the updated 2018 ASCO/CAP guidelines for testing in breast cancer as negative (0, 1+), equivocal (2+), or positive (3+). All cases which were scored as 2+, those with a discordant status (negative versus positive) between paired samples, and some more were tested by fluorescence in situ hybridization (FISH) for ERBB2 amplification status. A group of cases was also tested by NGS, comparing ERBB2 amplification as measured by NGS, IHC, and ISH.
RESULTS: 70 patients resulted eligible for the heterogeneity-part of the project: 45 biopsies, 68 hysterectomies, and 71 metastases (multiple metastatic lesions from the same patient were available in 24 of 42 cases). Using combined IHC/FISH, HER2 positive status was observed in 9 of 68 primary USC (13%). By IHC, paired biopsy and hysterectomy were discordant in 1/43 (2%). Hysterectomy or biopsy and metastasis pairs showed discordance in 8/42 (19%) cases, while multiple metastatic lesions from a same patient in 3/24 (7%). Heterogeneity in HER2 amplification (as defined by Buza) within a single stained slide was present in 4/45 biopsies (9%), 21/68 hysterectomies (31%) and 2/71 metastasis (3%).
93 patients resulted eligible for the second part of the project (NGS). Using combined IHC/FISH, ERBB2 amplification was observed in 8 of 93 cases (9%). NGS identified the same 8 cases with copy number ≥6; all 85 others had copy number <6.
CONCLUSIONS: Despite significant HER2 overexpression heterogeneity in over 30% of slides from hysterectomy specimens, there was excellent overall agreement (98%) in HER2 scores between paired biopsy and hysterectomy specimens. However, HER2 overexpression was discordant in 19% of hysterectomy-metastases pairs, suggesting that testing should be performed on a site of metastatic disease prior to the initiation of targeted therapy. In our series, NGS had 100% concordance with combined IHC/FISH in identifying ERBB2 amplification. NGS is highly accurate in detecting ERBB2 amplification in USC and provides an alternative to measurement by IHC and FISH.BACKGROUND: Uterine serous carcinoma (USC) is an aggressive tumor, responsible for approximately half of endometrial carcinoma-related mortality. A subset of USC shows HER2 overexpression due to ERBB2 amplification, and a recent phase 2 trial demonstrated that these patients benefit from treatment with trastuzumab. Therefore, accurate assessment of HER2 status is critical to properly select patients for targeted therapy. However, previous work has shown a significant intratumoral heterogeneity of ERBB2 amplification in USC and Next Generation Sequencing (NGS) is (and will be) increasingly used in the identification of targetable or clinically relevant (such as POLE point mutations) molecular alterations in endometrial carcinoma.
AIMS: To investigate the potential clinical impact of HER2 heterogeneity by examining HER2 status in paired endometrial biopsies, hysterectomy specimens, and metastatic lesions from patients with USC. To investigate the ability of a targeted NGS panel to detect ERBB2 amplification.
MATERIALS AND METHODS: Cases of USC were retrospectively identified, for which FFPE tumoral tissue was available (biopsy, hysterectomy, and/or metastasis specimen from the same patient). HER2 expression was assessed by immunohistochemistry (IHC) on all samples and scored using the updated 2018 ASCO/CAP guidelines for testing in breast cancer as negative (0, 1+), equivocal (2+), or positive (3+). All cases which were scored as 2+, those with a discordant status (negative versus positive) between paired samples, and some more were tested by fluorescence in situ hybridization (FISH) for ERBB2 amplification status. A group of cases was also tested by NGS, comparing ERBB2 amplification as measured by NGS, IHC, and ISH.
RESULTS: 70 patients resulted eligible for the heterogeneity-part of the project: 45 biopsies, 68 hysterectomies, and 71 metastases (multiple metastatic lesions from the same patient were available in 24 of 42 cases). Using combined IHC/FISH, HER2 positive status was observed in 9 of 68 primary USC (13%). By IHC, paired biopsy and hysterectomy were discordant in 1/43 (2%). Hysterectomy or biopsy and metastasis pairs showed discordance in 8/42 (19%) cases, while multiple metastatic lesions from a same patient in 3/24 (7%). Heterogeneity in HER2 amplification (as defined by Buza) within a single stained slide was present in 4/45 biopsies (9%), 21/68 hysterectomies (31%) and 2/71 metastasis (3%).
93 patients resulted eligible for the second part of the project (NGS). Using combined IHC/FISH, ERBB2 amplification was observed in 8 of 93 cases (9%). NGS identified the same 8 cases with copy number ≥6; all 85 others had copy number <6.
CONCLUSIONS: Despite significant HER2 overexpression heterogeneity in over 30% of slides from hysterectomy specimens, there was excellent overall agreement (98%) in HER2 scores between paired biopsy and hysterectomy specimens. However, HER2 overexpression was discordant in 19% of hysterectomy-metastases pairs, suggesting that testing should be performed on a site of metastatic disease prior to the initiation of targeted therapy. In our series, NGS had 100% concordance with combined IHC/FISH in identifying ERBB2 amplification. NGS is highly accurate in detecting ERBB2 amplification in USC and provides an alternative to measurement by IHC and FISH
RAS, Cellular Plasticity, and Tumor Budding in Colorectal Cancer
Full text linkThe high morbidity and mortality of colorectal cancer (CRC) remain a worldwide challenge, despite the advances in prevention, diagnosis, and treatment. RAS alterations have a central role in the pathogenesis of CRC universally recognized both in the canonical mutation-based classification and in the recent transcriptome-based classification. About 40% of CRCs are KRAS mutated, 5% NRAS mutated, and only rare cases are HRAS mutated. Morphological and molecular correlations demonstrated the involvement of RAS in cellular plasticity, which is related to invasive and migration properties of neoplastic cells. RAS signaling has been involved in the initiation of epithelial to mesenchymal transition (EMT) in CRC leading to tumor spreading. Tumor budding is the morphological surrogate of EMT and features cellular plasticity. Tumor budding is clinically relevant for CRC patients in three different contexts: (i) in pT1 CRC the presence of tumor buds is associated with nodal metastasis, (ii) in stage II CRC identifies the cases with a prognosis similar to metastatic disease, and (iii) intratumoral budding could be useful in patient selection for neoadjuvant therapy. This review is focused on the current knowledge on RAS in CRC and its link with cellular plasticity and related clinicopathological features
Histological criteria for age determination of fatal venous thromboembolism
Full text linkIn clinical and forensic practice, fatal thromboembolism is a major problem, particularly in a patient with no pre-existing risk factors. Out of a recent case, we discuss here the criteria for age determination of venous thrombi in a 46-year-old female with concomitant deep vein thrombosis in the common femoral left vein and in the right heart and fatal pulmonary embolism. At autopsy, histopathology and immunohistochemistry evidenced the different composition of thrombi in different sites and permitted to define the different timing. We discuss and review the histopathological criteria for age estimation of venous thrombi starting from the case and in relation to the acquired and inherited thrombophilic risk factors. The appropriateness of clinical management is also discussed
Tumour budding seems to be independent to epithelial-mesenchymal transition in intestinal-type sinonasal adenocarcinoma
No full textMetastases of Uterine Serous Carcinoma Often Show a HER2 Expression Profile Different from the Biopsy and Hysterectomy Specimens
No full text
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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