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  • 1
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    Tumor mutational burden assessment in non-small-cell lung cancer samples: results from the TMB 2 harmonization project comparing three NGS panels
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. 5 ( 2021-05), p. e001904-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. 5 ( 2021-05), p. e001904-
    Kurzfassung: Tumor mutational burden (TMB) is a recently proposed predictive biomarker for immunotherapy in solid tumors, including non-small cell lung cancer (NSCLC). Available assays for TMB determination differ in horizontal coverage, gene content and algorithms, leading to discrepancies in results, impacting patient selection. A harmonization study of TMB assessment with available assays in a cohort of patients with NSCLC is urgently needed. Methods We evaluated the TMB assessment obtained with two marketed next generation sequencing panels: TruSight Oncology 500 (TSO500) and Oncomine Tumor Mutation Load (OTML) versus a reference assay (Foundation One, FO) in 96 NSCLC samples. Additionally, we studied the level of agreement among the three methods with respect to PD-L1 expression in tumors, checked the level of different immune infiltrates versus TMB, and performed an inter-laboratory reproducibility study. Finally, adjusted cut-off values were determined. Results Both panels showed strong agreement with FO, with concordance correlation coefficients (CCC) of 0.933 (95% CI 0.908 to 0.959) for TSO500 and 0.881 (95% CI 0.840 to 0.922) for OTML. The corresponding CCCs were 0.951 (TSO500-FO) and 0.919 (OTML-FO) in tumors with 〈 1% of cells expressing PD-L1 (PD-L1 〈 1%; N = 55), and 0.861 (TSO500-FO) and 0.722 (OTML-FO) in tumors with PD-L1≥1% (N=41). Inter-laboratory reproducibility analyses showed higher reproducibility with TSO500. No significant differences were found in terms of immune infiltration versus TMB. Adjusted cut-off values corresponding to 10 muts/Mb with FO needed to be lowered to 7.847 muts/Mb (TSO500) and 8.380 muts/Mb (OTML) to ensure a sensitivity 〉 88%. With these cut-offs, the positive predictive value was 78.57% (95% CI 67.82 to 89.32) and the negative predictive value was 87.50% (95% CI 77.25 to 97.75) for TSO500, while for OTML they were 73.33% (95% CI 62.14 to 84.52) and 86.11% (95% CI 74.81 to 97.41), respectively. Conclusions Both panels exhibited robust analytical performances for TMB assessment, with stronger concordances in patients with negative PD-L1 expression. TSO500 showed a higher inter-laboratory reproducibility. The cut-offs for each assay were lowered to optimal overlap with FO.
    Materialart: Online-Ressource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2020-001904
    Sprache: Englisch
    Verlag: BMJ
    Publikationsdatum: 2021
    ZDB Id: 2719863-7
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  • 2
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    Table_1.DOCX
    Frontiers Media SA ; 2022
    In:  Frontiers in Microbiology Vol. 13 ( 2022-1-31)
    Details
    In: Frontiers in Microbiology, Frontiers Media SA, Vol. 13 ( 2022-1-31)
    Kurzfassung: The exact role of viral replication in patients with severe COVID-19 has not been extensively studied, and it has only been possible to demonstrate the presence of replicative virus for more than 3 months in a few cases using different techniques. Our objective was to study the presence of RNA SARS-CoV-2 in autopsy samples of patients who died from COVID-19 long after the onset of symptoms. Secondary superimposed pulmonary infections present in these patients were also studied. We present an autopsy series of 27 COVID-19 patients with long disease duration, where pulmonary and extrapulmonary samples were obtained. In addition to histopathological analysis, viral genomic RNA (gRNA) and viral subgenomic RNA (sgRNA) were detected using RT-PCR and in situ hybridization, and viral protein was detected using immunohistochemistry. This series includes 26 adults with a median duration of 39 days from onset of symptoms to death (ranging 9–108 days), 92% of them subjected to immunomodulatory therapy, and an infant patient. We detected gRNA in the lung of all but one patient, including those with longer disease duration. SgRNA was detected in 11 out of 17 patients (64.7%) with illness duration up to 6 weeks and in 3 out of 9 patients (33.3%) with more than 6 weeks of disease progression. Viral protein was detected using immunohistochemistry and viral mRNA was detected using in situ hybridization in 3 out of 4 adult patients with illness duration of & lt;2 weeks, but in none of the 23 adult patients with an illness duration of & gt;2 weeks. A remarkable result was the detection of viral protein, gRNA and sgRNA in the lung cells of the pediatric patient after 95 days of illness. Additional pulmonary infections included: 9 acute bronchopneumonia, 2 aspergillosis, 2 cytomegalovirus, and 1 BK virus infection. These results suggest that in severe COVID-19, SARS-CoV-2 could persist for longer periods than expected, especially in immunocompromised populations, contributing to the persistence of chronic lung lesions. Additional infections contribute to the fatal course of the disease.
    Materialart: Online-Ressource
    ISSN: 1664-302X
    URL: Article
    URL: Article
    DOI: 10.3389/fmicb.2022.824967
    DOI: 10.3389/fmicb.2022.824967.s001
    Sprache: Unbekannt
    Verlag: Frontiers Media SA
    Publikationsdatum: 2022
    ZDB Id: 2587354-4
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  • 3
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    Identification of Trim24 as a new NTRK3 fusion partner in lung adenocarcinoma: Diagnostic challenges of a novel fusion
    Elsevier BV ; 2022
    In:  Human Pathology Reports Vol. 28 ( 2022-06), p. 300625-
    Details
    In: Human Pathology Reports, Elsevier BV, Vol. 28 ( 2022-06), p. 300625-
    Materialart: Online-Ressource
    ISSN: 2772-736X
    URL: Article
    DOI: 10.1016/j.hpr.2022.300625
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2022
    ZDB Id: 3120751-0
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  • 4
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    Epigenetic Fingerprint of the SARS-CoV-2 Infection in the Lung of Lethal COVID-19
    Elsevier BV ; 2023
    In:  CHEST ( 2023-10)
    Details
    In: CHEST, Elsevier BV, ( 2023-10)
    Materialart: Online-Ressource
    ISSN: 0012-3692
    URL: Article
    DOI: 10.1016/j.chest.2023.10.032
    RVK:
    XA 36340
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2023
    ZDB Id: 2007244-2
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
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    Molecular Heterogeneity of High Grade Colorectal Adenocarcinoma
    MDPI AG ; 2021
    In:  Cancers Vol. 13, No. 2 ( 2021-01-10), p. 233-
    Details
    In: Cancers, MDPI AG, Vol. 13, No. 2 ( 2021-01-10), p. 233-
    Kurzfassung: High grade colorectal carcinomas (HG-CRCs), which comprise 15% of colorectal carcinomas, are underrepresented in reported molecular studies. Clinicopathological, immunohistochemical, and molecular features of 40 HG-CRCs are described. Moreover, glandular and solid areas of 25 tumors were separately analyzed. The expression of MLH1, PMS2, MSH2, MSH6, p53, E-cadherin, CDX2, CK20, CD8, PDL1, PAN-TRK, c-MET, SMARCB1, ARID1A, SMARCA2, and SMARCA4 was analyzed by immunohistochemistry. Promoter MLH1 methylation was analyzed in tumors with MLH1/PMS2 loss. Next-generation sequencing was used to screen 161 genes for hotspot mutations, copy number variations and gene fusions. In this series, 72.5% of HG-CRCs showed mismatch repair deficiency (MMRd). MMR deficient tumor and MMR proficient (MMRp) tumors showed striking molecular differences. Thus, whereas BRAF mutations were only observed in MMRd tumors, mutations in KRAS and TP53 were more frequent in MMR proficient tumors. Moreover, gene fusions (NTRK1 and MET) were detected only in MMRd tumors, whereas gene amplification (MYC, CCND1 and EGFR) predominated in MMRp/TP53-mutated tumors. Loss of expression of proteins involved in chromatin remodeling, such as ARID1A, was observed only in MMRd HG-CRCs, which also showed more frequently PD-L1 expression and a higher number of tumor infiltrating lymphocytes. The separate analysis of glandular and solid areas indicated that the clonal or subclonal nature of the molecular alterations also depended on MMR status. Mutations in genes such as TP53 and KRAS were always clonal in MMRp-CRCs but occurred as subclonal events in MMRd-CRCs. Gene amplification was implicated in the progression of MMRp tumors, but not in MMRd tumors, in which clonal diversity was due to accumulation of mutations in genes of different pathways such as NOTCH, MMR, or PIK3CA. In summary, intertumor and intratumor molecular heterogeneity in HG-CRCs is mainly due to MMR status.
    Materialart: Online-Ressource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers13020233
    Sprache: Englisch
    Verlag: MDPI AG
    Publikationsdatum: 2021
    ZDB Id: 2527080-1
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  • 6
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    Mismatch Repair Deficiency in Ovarian Carcinoma : Frequency, Causes, and Consequences
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  American Journal of Surgical Pathology Vol. 44, No. 5 ( 2020-05), p. 649-656
    Details
    In: American Journal of Surgical Pathology, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. 5 ( 2020-05), p. 649-656
    Kurzfassung: Mismatch repair deficiency (MMRD) is involved in the initiation of both hereditary and sporadic tumors. MMRD has been extensively studied in colorectal cancer and endometrial cancer, but not so in other tumors, such as ovarian carcinoma. We have determined the expression of mismatch repair proteins in a large cohort of 502 early-stage epithelial ovarian carcinoma entailing all the 5 main subtypes: high-grade serous carcinoma, endometrioid ovarian carcinoma (EOC), clear cell carcinoma (CCC), mucinous carcinoma, and low-grade serous carcinoma. We studied the association of MMRD with clinicopathologic and immunohistochemical features, including tumor-infiltrating lymphocytes in EOC, the histologic type in which MMRD is most frequent. In addition, MLH1 promoter methylation status and massive parallel sequencing were used to evaluate the proportion of sporadic and Lynch syndrome–associated tumors, and the most frequently mutated genes in MMRD EOCs. MMRD occurred only in endometriosis-associated histologic types, and it was much more frequent in EOC (18%) than in CCC (2%). The most frequent immunohistochemical pattern was loss of MLH1/PMS2, and in this group, 80% of the cases were sporadic and secondary to MLH1 promoter hypermethylation. The presence of somatic mutations in mismatch repair genes was the other mechanism of MMRD in sporadic tumors. In this series, the minimum estimated frequency of Lynch syndrome was 35% and it was due to germline mutations in MLH1 , MSH2 , and MSH6. ARID1A , PTEN , KTM2B , and PIK3CA were the most common mutated genes in this series. Interestingly, possible actionable mutations in ERRB2 were found in 5 tumors, but no TP53 mutations were detected. MMRD was associated with younger age and increased tumor-infiltrating lymphocytes. Universal screening in EOC and mixed EOC/CCC is recommended for the high frequency of MMRD detected; however, for CCC, additional clinical and pathologic criteria should be evaluated to help select cases for analysis.
    Materialart: Online-Ressource
    ISSN: 0147-5185
    URL: Article
    DOI: 10.1097/PAS.0000000000001432
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2020
    ZDB Id: 2029143-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
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    Molecular Heterogeneity of Endometrioid Ovarian Carcinoma : An Analysis of 166 Cases Using the Endometrial Cancer Subrogate Molecular Classification
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  American Journal of Surgical Pathology Vol. 44, No. 7 ( 2020-07), p. 982-990
    Details
    In: American Journal of Surgical Pathology, Ovid Technologies (Wolters Kluwer Health), Vol. 44, No. 7 ( 2020-07), p. 982-990
    Kurzfassung: Endometrioid ovarian carcinoma (EOC) has clinical and biological differences compared with other histologic types of ovarian carcinomas, but it shares morphologic and molecular features with endometrioid endometrial carcinoma. To analyze the molecular heterogeneity of EOC according to the new molecular classification of endometrial cancer and to evaluate the prognostic significance of this molecular classification, we have analyzed 166 early-stage EOC by immunohistochemistry for mismatch repair proteins and p53 expression, and by Sanger sequencing for the exonuclease domain of polymerase epsilon ( POLE EDM ). In addition, we have carried out next-generation sequencing analysis of tumors with POLE EDM mutations to confirm the ultramutated profile. Eight tumors carried POLE EDM mutations and were classified as ultramutated (5%), 29 showed mismatch repair deficiency and were classified as hypermutated (18%), 16 tumors had a mutated pattern of p53 expression and were classified as p53 abnormal (11%), and 114 tumors did not have any of the previous alterations and were classified as no specific type (66%). Five tumors showed 〉 1 classification criteria. The frequencies of ultramutated and hypermutated tumors were lower in EOC compared with the frequency reported in endometrial cancer. Subrogate molecular groups differed in both morphologic features (histologic grade, squamous and morular metaplasia, and necrosis) and immunohistochemical expression of several biomarkers (ARID1A, nuclear β-catenin, estrogen receptors, Napsin A, and HINF1B). In addition, the number of CD8 + tumor-infiltrating lymphocytes was higher in ultramutated and hypermutated tumors. The most commonly mutated genes in the ultramutated group were ARID1A (100%), PIK3R1 , PTEN , BCOR , and TP53 (67% each), whereas no mutations were detected in KRAS. Although the prognosis did not differ among subgroups in the multivariate analysis, a trend toward a better prognosis in POLE -mutated and a worse prognosis in p53 abnormal tumors was observed. In addition, this classification could have important therapeutic implications for the use of immunotherapy in tumors classified as ultramutated and hypermutated.
    Materialart: Online-Ressource
    ISSN: 0147-5185
    URL: Article
    DOI: 10.1097/PAS.0000000000001478
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2020
    ZDB Id: 2029143-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
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    Next generation sequencing to decipher concurrent loss of PMS2 and MSH6 in colorectal cancer
    Springer Science and Business Media LLC ; 2020
    In:  Diagnostic Pathology Vol. 15, No. 1 ( 2020-12)
    Details
    In: Diagnostic Pathology, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2020-12)
    Kurzfassung: Immunohistochemistry (IHQ) is commonly used for the detection of mismatch repair proteins deficiency (MMRD). One very infrequent abnormal pattern of MMR protein expression is the loss of PMS2 and MSH6, with intact expression of MLH1 and MSH2. Case presentation We review the frequency of this MMRD IHC pattern among 108 colorectal (CRCs) and 35 endometrial cancers in our files with loss of expression of at least one protein, and present two CRCs showing loss of PMS2 and MSH6 protein expression (1.9% of CRCs). NGS analysis of these tumours identified PMS2 mutations (R134* germline mutation in one tumour and M1R and c.1239delA somatic mutation in the other) as the primary event and somatic MSH6 mutation (c.3261dupC) as the secondary event in both tumours. Conclusions This study suggests that Next Generation Sequencing (NGS) tumour analysis should be considered in the algorithm of Lynch syndrome screening to detect MMR gen somatic mutation in inconclusive cases.
    Materialart: Online-Ressource
    ISSN: 1746-1596
    URL: Article
    DOI: 10.1186/s13000-020-01001-2
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2020
    ZDB Id: 2210518-9
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
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    Vulvar Pilomatrix Carcinoma: Morphologic and Molecular Features
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  International Journal of Gynecological Pathology Vol. 40, No. 5 ( 2021-09), p. 482-486
    Details
    In: International Journal of Gynecological Pathology, Ovid Technologies (Wolters Kluwer Health), Vol. 40, No. 5 ( 2021-09), p. 482-486
    Kurzfassung: Pilomatrix carcinoma (PC) is a rare malignant variant of pilomatrixoma, a skin adnexal tumor originating from hair matrix cells. It is most often located in the head, neck region, upper back and upper extremities. PC has a locally aggressive behavior but metastasis only occur in 10% of cases. Mutations in CTNNB1 , the encoding gene of beta-catenin, have been found in both pilomatrixoma and PC, but other molecular alterations are unknown. The authors present a case of PC in the clitoris, the third known reported case located on the external genitalia. The tumor followed an unusual clinical course with the development of multiple metastases. Next-generation sequencing analysis of the tumor identified, in addition to a characteristic CTNNB1 mutation, pathogenic mutations in PTEN , PIK3CA , and ARID1A , which could explain the aggressive course of the disease. The diagnostic criteria of PC and the differential diagnoses of this unusual tumor in the genital area are discussed.
    Materialart: Online-Ressource
    ISSN: 0277-1691
    URL: Article
    DOI: 10.1097/PGP.0000000000000726
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2021
    ZDB Id: 2071024-0
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
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    Epithelial Mesenchymal Transition and Immune Response in Metaplastic Breast Carcinoma
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 14 ( 2021-07-09), p. 7398-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 14 ( 2021-07-09), p. 7398-
    Kurzfassung: Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent triple negative (TN) invasive carcinomas with poor prognosis. MBCs have a different clinical behavior from other types of triple negative breast cancer (TNBC), being more resistant to standard chemotherapy. MBCs are an example of tumors with activation of epithelial–mesenchymal transition (EMT). The mechanisms involved in EMT could be responsible for the increase in the infiltrative and metastatic capacity of MBCs and resistance to treatments. In addition, a relationship between EMT and the immune response has been seen in these tumors. In this sense, MBC differ from other TN tumors showing a lower number of tumor-infiltrating lymphocytes (TILS) and a higher percentage of tumor cells expressing programmed death-ligand 1 (PD-L1). A better understanding of the relationship between the immune system and EMT could provide new therapeutic approaches in MBC.
    Materialart: Online-Ressource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22147398
    Sprache: Englisch
    Verlag: MDPI AG
    Publikationsdatum: 2021
    ZDB Id: 2019364-6
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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