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  • 1
    Online Resource
    Online Resource
    Integration of p16/HPV DNA Status with a 24-miRNA-Defined Molecular Phenotype Improves Clinically Relevant Stratification of Head and Neck Cancer Patients
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 15 ( 2022-07-31), p. 3745-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 15 ( 2022-07-31), p. 3745-
    Abstract: Human papillomavirus (HPV)-driven head and neck squamous cell carcinomas (HNSCC) generally have a more favourable prognosis. We hypothesized that HPV-associated HNSCC may be identified by an miRNA-signature according to their specific molecular pathogenesis, and be characterized by a unique transcriptome compared to HPV-negative HNSCC. We performed miRNA expression profiling of two p16/HPV DNA characterized HNSCC cohorts of patients treated by adjuvant radio(chemo)therapy (multicentre DKTK-ROG n = 128, single-centre LMU-KKG n = 101). A linear model predicting HPV status built in DKTK-ROG using lasso-regression was tested in LMU-KKG. LMU-KKG tumours (n = 30) were transcriptome profiled for differential gene expression and miRNA-integration. A 24-miRNA signature predicted HPV-status with 94.53% accuracy (AUC: 0.99) in DKTK-ROG, and 86.14% (AUC: 0.86) in LMU-KKG. The prognostic values of 24-miRNA- and p16/HPV DNA status were comparable. Combining p16/HPV DNA and 24-miRNA status allowed patient sub-stratification and identification of an HPV-associated patient subgroup with impaired overall survival. HPV-positive tumours showed downregulated MAPK, Estrogen, EGFR, TGFbeta, WNT signaling activity. miRNA-mRNA integration revealed HPV-specific signaling pathway regulation, including PD−L1 expression/PD−1 checkpoint pathway in cancer in HPV-associated HNSCC. Integration of clinically established p16/HPV DNA with 24-miRNA signature status improved clinically relevant risk stratification, which might be considered for future clinical decision-making with respect to treatment de-escalation in HPV-associated HNSCC.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14153745
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 2
    Online Resource
    Online Resource
    A Five-MicroRNA Signature Predicts Survival and Disease Control of Patients with Head and Neck Cancer Negative for HPV Infection
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 5 ( 2019-03-01), p. 1505-1516
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 5 ( 2019-03-01), p. 1505-1516
    Abstract: Human papillomavirus (HPV)–negative head and neck squamous cell carcinoma (HNSCC) is associated with unfavorable prognosis, while independent prognostic markers remain to be defined. Experimental Design: We retrospectively performed miRNA expression profiling. Patients were operated for locally advanced HPV-negative HNSCC and had received radiochemotherapy in eight different hospitals (DKTK-ROG; n = 85). Selection fulfilled comparable demographic, treatment, and follow-up characteristics. Findings were validated in an independent single-center patient sample (LMU-KKG; n = 77). A prognostic miRNA signature was developed for freedom from recurrence and tested for other endpoints. Recursive-partitioning analysis was performed on the miRNA signature, tumor and nodal stage, and extracapsular nodal spread. Technical validation used qRT-PCR. An miRNA–mRNA target network was generated and analyzed. Results: For DKTK-ROG and LMU-KKG patients, the median follow-up was 5.1 and 5.3 years, and the 5-year freedom from recurrence rate was 63.5% and 75.3%, respectively. A five-miRNA signature (hsa-let-7g-3p, hsa-miR-6508-5p, hsa-miR-210-5p, hsa-miR-4306, and hsa-miR-7161-3p) predicted freedom from recurrence in DKTK-ROG [hazard ratio (HR) 4.42; 95% confidence interval (CI), 1.98−9.88, P & lt; 0.001], which was confirmed in LMU-KKG (HR 4.24; 95% CI, 1.40−12.81, P = 0.005). The signature also predicted overall survival (HR 3.03; 95% CI, 1.50−6.12, P = 0.001), recurrence-free survival (HR 3.16; 95% CI, 1.65−6.04, P & lt; 0.001), and disease-specific survival (HR 5.12; 95% CI, 1.88−13.92, P & lt; 0.001), all confirmed in LMU-KKG data. Adjustment for relevant covariates maintained the miRNA signature predicting all endpoints. Recursive-partitioning analysis of both samples combined classified patients into low (n = 17), low-intermediate (n = 80), high-intermediate (n = 48), or high risk (n = 17) for recurrence (P & lt; 0.001). Conclusions: The five-miRNA signature is a strong and independent prognostic factor for disease recurrence and survival of patients with HPV-negative HNSCC. See related commentary by Clump et al., p. 1441
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-18-0776
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
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    Challenges, facilitators and barriers to screening study participants in early disease stages-experience from the MACUSTAR study
    Springer Science and Business Media LLC ; 2021
    In:  BMC Medical Research Methodology Vol. 21, No. 1 ( 2021-12)
    Details
    In: BMC Medical Research Methodology, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2021-12)
    Abstract: Recruiting asymptomatic participants with early disease stages into studies is challenging and only little is known about facilitators and barriers to screening and recruitment of study participants. Thus we assessed factors associated with screening rates in the MACUSTAR study, a multi-centre, low-interventional cohort study of early stages of age-related macular degeneration (AMD). Methods Screening rates per clinical site and per week were compiled and applicable recruitment factors were assigned to respective time periods. A generalized linear mixed-effects model including the most relevant recruitment factors identified via in-depth interviews with study personnel was fitted to the screening data. Only participants with intermediate AMD were considered. Results A total of 766 individual screenings within 87 weeks were available for analysis. The mean screening rate was 0.6 ± 0.9 screenings per week among all sites. The participation at investigator teleconferences (relative risk increase 1.466, 95% CI [1.018–2.112]), public holidays (relativ e risk decrease 0.466, 95% CI [0.367–0.591]) and reaching 80% of the site’s recruitment target (relative risk decrease 0.699, 95% CI [0.367–0.591] ) were associated with the number of screenings at an individual site level. Conclusions Careful planning of screening activities is necessary when recruiting early disease stages in multi-centre observational or low-interventional studies. Conducting teleconferences with local investigators can increase screening rates. When planning recruitment, seasonal and saturation effects at clinical site level need to be taken into account. Trial registration ClinicalTrials.gov NCT03349801 . Registered on 22 November 2017.
    Type of Medium: Online Resource
    ISSN: 1471-2288
    URL: Article
    DOI: 10.1186/s12874-021-01243-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2041362-2
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  • 4
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    Online Resource
    A prognostic mRNA expression signature of four 16q24.3 genes in radio(chemo)therapy‐treated head and neck squamous cell carcinoma (HNSCC)
    Wiley ; 2018
    In:  Molecular Oncology Vol. 12, No. 12 ( 2018-12), p. 2085-2101
    Details
    In: Molecular Oncology, Wiley, Vol. 12, No. 12 ( 2018-12), p. 2085-2101
    Abstract: Previously, we have shown that copy number gain of the chromosomal band 16q24.3 is associated with impaired clinical outcome of radiotherapy‐treated head and neck squamous cell carcinoma ( HNSCC ) patients. We set out to identify a prognostic mRNA signature from genes located on 16q24.3 in radio(chemo)therapy‐treated HNSCC patients of the TCGA (The Cancer Genome Atlas, n  = 99) cohort. We applied stepwise forward selection using expression data of 41 16q24.3 genes. The resulting optimal Cox‐proportional hazards regression model included the genes APRT , CENPBD 1, CHMP 1A, and GALNS . Afterward, the prognostic value of the classifier was confirmed in an independent cohort of HNSCC patients treated by adjuvant radio(chemo)therapy ( LMU ‐ KKG cohort). The signature significantly differentiated high‐ and low‐risk patients with regard to overall survival ( HR  = 2.01, 95% CI 1.10–3.70; P  = 0.02125), recurrence‐free survival ( HR  = 1.84, 95% CI 1.01–3.34; P  = 0.04206), and locoregional recurrence‐free survival ( HR  = 1.87, 95% CI 1.03–3.40; P  = 0.03641). The functional impact of the four signature genes was investigated after reconstruction of a gene association network from transcriptome data of the TCGA HNSCC cohort using a partial correlation approach. Subsequent pathway enrichment analysis of the network neighborhood (first and second) of the signature genes suggests involvement of HNSCC ‐associated signaling pathways such as apoptosis, cell cycle, cell adhesion, EGFR , JAK ‐ STAT , and mTOR . Furthermore, a detailed analysis of the first neighborhood revealed a cluster of co‐expressed genes located on chromosome 16q, substantiating the impact of 16q24.3 alterations in poor clinical outcome of HNSCC . The reported gene expression signature represents a prognostic marker in HNSCC patients following postoperative radio(chemo)therapy.
    Type of Medium: Online Resource
    ISSN: 1574-7891 , 1878-0261
    URL: Issue
    URL: Article
    DOI: 10.1002/mol2.2018.12.issue-12
    DOI: 10.1002/1878-0261.12388
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2322586-5
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  • 5
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    Online Resource
    Repeatability and Discriminatory Power of Chart-Based Visual Function Tests in Individuals With Age-Related Macular Degeneration : A MACUSTAR Study Report
    American Medical Association (AMA) ; 2022
    In:  JAMA Ophthalmology Vol. 140, No. 8 ( 2022-08-01), p. 780-
    Details
    In: JAMA Ophthalmology, American Medical Association (AMA), Vol. 140, No. 8 ( 2022-08-01), p. 780-
    Abstract: There is a need for validated clinical end points that are reliably able to quantify potential therapeutic effects of future treatments targeting age-related macular degeneration (AMD) before the onset of serious visual impairment. Objective To assess the reliability and discriminatory power of 5 simple chart-based visual function (VF) tests as potential measures for clinical trial end points with regulatory and patient-access intention in intermediate AMD (iAMD). Design, Setting, and Participants This international noninterventional study took place at 18 tertiary ophthalmology departments across Europe. Participants were recruited between April 2018 and March 2020 and were identified during routine clinical review. Participants with no AMD and early AMD were recruited from hospital staff, friends, and family of participants with AMD and via referrals from community ophthalmologists and optometrists. The repeatability and discriminatory power of 5 simple chart-based assessments of VF (best-corrected visual acuity [BCVA], low-luminance visual acuity [LLVA] , Moorfields Acuity Test [MAT], Pelli-Robson Contrast Sensitivity [CS] , and International Reading Speed Test [IReST]) were assessed in a repeated-measures design. VF assessments were performed on day 0 and day 14. Participants with early AMD, iAMD, late AMD, and no AMD were recruited. Main Outcomes and Measures Intraclass correlation coefficients (ICCs) and Bland-Altman 95% limits of agreement (LoA) were computed to assess repeatability. Area under the receiver operating characteristic curves (AUCs) determined the discriminatory ability of all measures to classify individuals as having no AMD or iAMD and to differentiate iAMD from its neighboring disease states. Results A total of 301 participants (mean [SD] age, 71 [7] years; 187 female participants [62.1%]) were included in the study. Thirty-four participants (11.3%) had early AMD, 168 (55.8%) had iAMD, 43 (14.3%) had late AMD, and 56 (18.6%) had no AMD. ICCs for all VF measures ranged between 0.88 and 0.96 when all participants were considered, indicating good to excellent repeatability. All measures displayed excellent discrimination between iAMD and late AMD (AUC, 0.92-0.99). Early AMD was indistinguishable from iAMD on all measures (AUC, 0.54-0.64). CS afforded the best discrimination between no AMD and iAMD (AUC, 0.77). Under the same conditions, BCVA, LLVA, and MAT were fair discriminators (AUC, 0.69-0.71), and IReST had poor discrimination (AUC, 0.57-0.61). Conclusions and Relevance BCVA, LLVA, MAT, CS, and IReST had adequate repeatability in this multicenter, multiexaminer setting but limited power to discriminate between no AMD and iAMD. The prognostic power of these variables to predict conversion from iAMD to late AMD is being examined in the ongoing longitudinal part of the MACUSTAR study.
    Type of Medium: Online Resource
    ISSN: 2168-6165
    URL: Article
    DOI: 10.1001/jamaophthalmol.2022.2113
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
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