Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma
Introduction Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP...
Ausführliche Beschreibung
Autor*in: |
Mayura Meerang [verfasserIn] Karima Bérard [verfasserIn] Martina Friess [verfasserIn] Byron K.Y. Bitanihirwe [verfasserIn] Alex Soltermann [verfasserIn] Bart Vrugt [verfasserIn] Emanuela Felley-Bosco [verfasserIn] Raphael Bueno [verfasserIn] William G. Richards [verfasserIn] Burkhardt Seifert [verfasserIn] Rolf Stahel [verfasserIn] Walter Weder [verfasserIn] Isabelle Opitz [verfasserIn] |
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E-Artikel |
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Englisch |
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2016 |
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In: Molecular Oncology - Wiley, 2017, 10(2016), 8, Seite 1255-1265 |
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volume:10 ; year:2016 ; number:8 ; pages:1255-1265 |
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DOI / URN: |
10.1016/j.molonc.2016.06.005 |
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DOAJ095543929 |
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245 | 1 | 0 | |a Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma |
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520 | |a Introduction Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methods Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre‐ and post‐CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H‐score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Results Kaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre‐induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post‐CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre‐ and post‐CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3–0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3–1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7–6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27–4.33, p = 0.006]. Conclusions Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment. | ||
650 | 4 | |a Merlin | |
650 | 4 | |a Hippo pathway | |
650 | 4 | |a Survivin | |
650 | 4 | |a Malignant pleural mesothelioma | |
650 | 4 | |a Multimodality treatment | |
653 | 0 | |a Neoplasms. Tumors. Oncology. Including cancer and carcinogens | |
700 | 0 | |a Karima Bérard |e verfasserin |4 aut | |
700 | 0 | |a Martina Friess |e verfasserin |4 aut | |
700 | 0 | |a Byron K.Y. Bitanihirwe |e verfasserin |4 aut | |
700 | 0 | |a Alex Soltermann |e verfasserin |4 aut | |
700 | 0 | |a Bart Vrugt |e verfasserin |4 aut | |
700 | 0 | |a Emanuela Felley-Bosco |e verfasserin |4 aut | |
700 | 0 | |a Raphael Bueno |e verfasserin |4 aut | |
700 | 0 | |a William G. Richards |e verfasserin |4 aut | |
700 | 0 | |a Burkhardt Seifert |e verfasserin |4 aut | |
700 | 0 | |a Rolf Stahel |e verfasserin |4 aut | |
700 | 0 | |a Walter Weder |e verfasserin |4 aut | |
700 | 0 | |a Isabelle Opitz |e verfasserin |4 aut | |
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10.1016/j.molonc.2016.06.005 doi (DE-627)DOAJ095543929 (DE-599)DOAJ12c600ed6875413da0735385b2c80c20 DE-627 ger DE-627 rakwb eng RC254-282 Mayura Meerang verfasserin aut Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Introduction Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methods Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre‐ and post‐CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H‐score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Results Kaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre‐induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post‐CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre‐ and post‐CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3–0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3–1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7–6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27–4.33, p = 0.006]. Conclusions Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment. Merlin Hippo pathway Survivin Malignant pleural mesothelioma Multimodality treatment Neoplasms. Tumors. Oncology. Including cancer and carcinogens Karima Bérard verfasserin aut Martina Friess verfasserin aut Byron K.Y. Bitanihirwe verfasserin aut Alex Soltermann verfasserin aut Bart Vrugt verfasserin aut Emanuela Felley-Bosco verfasserin aut Raphael Bueno verfasserin aut William G. Richards verfasserin aut Burkhardt Seifert verfasserin aut Rolf Stahel verfasserin aut Walter Weder verfasserin aut Isabelle Opitz verfasserin aut In Molecular Oncology Wiley, 2017 10(2016), 8, Seite 1255-1265 (DE-627)531199800 (DE-600)2322586-5 18780261 nnns volume:10 year:2016 number:8 pages:1255-1265 https://doi.org/10.1016/j.molonc.2016.06.005 kostenfrei https://doaj.org/article/12c600ed6875413da0735385b2c80c20 kostenfrei https://doi.org/10.1016/j.molonc.2016.06.005 kostenfrei https://doaj.org/toc/1574-7891 Journal toc kostenfrei https://doaj.org/toc/1878-0261 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2016 8 1255-1265 |
spelling |
10.1016/j.molonc.2016.06.005 doi (DE-627)DOAJ095543929 (DE-599)DOAJ12c600ed6875413da0735385b2c80c20 DE-627 ger DE-627 rakwb eng RC254-282 Mayura Meerang verfasserin aut Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Introduction Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methods Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre‐ and post‐CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H‐score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Results Kaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre‐induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post‐CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre‐ and post‐CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3–0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3–1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7–6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27–4.33, p = 0.006]. Conclusions Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment. Merlin Hippo pathway Survivin Malignant pleural mesothelioma Multimodality treatment Neoplasms. Tumors. Oncology. Including cancer and carcinogens Karima Bérard verfasserin aut Martina Friess verfasserin aut Byron K.Y. Bitanihirwe verfasserin aut Alex Soltermann verfasserin aut Bart Vrugt verfasserin aut Emanuela Felley-Bosco verfasserin aut Raphael Bueno verfasserin aut William G. Richards verfasserin aut Burkhardt Seifert verfasserin aut Rolf Stahel verfasserin aut Walter Weder verfasserin aut Isabelle Opitz verfasserin aut In Molecular Oncology Wiley, 2017 10(2016), 8, Seite 1255-1265 (DE-627)531199800 (DE-600)2322586-5 18780261 nnns volume:10 year:2016 number:8 pages:1255-1265 https://doi.org/10.1016/j.molonc.2016.06.005 kostenfrei https://doaj.org/article/12c600ed6875413da0735385b2c80c20 kostenfrei https://doi.org/10.1016/j.molonc.2016.06.005 kostenfrei https://doaj.org/toc/1574-7891 Journal toc kostenfrei https://doaj.org/toc/1878-0261 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2016 8 1255-1265 |
allfields_unstemmed |
10.1016/j.molonc.2016.06.005 doi (DE-627)DOAJ095543929 (DE-599)DOAJ12c600ed6875413da0735385b2c80c20 DE-627 ger DE-627 rakwb eng RC254-282 Mayura Meerang verfasserin aut Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Introduction Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methods Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre‐ and post‐CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H‐score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Results Kaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre‐induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post‐CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre‐ and post‐CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3–0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3–1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7–6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27–4.33, p = 0.006]. Conclusions Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment. Merlin Hippo pathway Survivin Malignant pleural mesothelioma Multimodality treatment Neoplasms. Tumors. Oncology. Including cancer and carcinogens Karima Bérard verfasserin aut Martina Friess verfasserin aut Byron K.Y. Bitanihirwe verfasserin aut Alex Soltermann verfasserin aut Bart Vrugt verfasserin aut Emanuela Felley-Bosco verfasserin aut Raphael Bueno verfasserin aut William G. Richards verfasserin aut Burkhardt Seifert verfasserin aut Rolf Stahel verfasserin aut Walter Weder verfasserin aut Isabelle Opitz verfasserin aut In Molecular Oncology Wiley, 2017 10(2016), 8, Seite 1255-1265 (DE-627)531199800 (DE-600)2322586-5 18780261 nnns volume:10 year:2016 number:8 pages:1255-1265 https://doi.org/10.1016/j.molonc.2016.06.005 kostenfrei https://doaj.org/article/12c600ed6875413da0735385b2c80c20 kostenfrei https://doi.org/10.1016/j.molonc.2016.06.005 kostenfrei https://doaj.org/toc/1574-7891 Journal toc kostenfrei https://doaj.org/toc/1878-0261 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2016 8 1255-1265 |
allfieldsGer |
10.1016/j.molonc.2016.06.005 doi (DE-627)DOAJ095543929 (DE-599)DOAJ12c600ed6875413da0735385b2c80c20 DE-627 ger DE-627 rakwb eng RC254-282 Mayura Meerang verfasserin aut Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Introduction Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methods Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre‐ and post‐CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H‐score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Results Kaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre‐induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post‐CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre‐ and post‐CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3–0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3–1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7–6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27–4.33, p = 0.006]. Conclusions Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment. Merlin Hippo pathway Survivin Malignant pleural mesothelioma Multimodality treatment Neoplasms. Tumors. Oncology. Including cancer and carcinogens Karima Bérard verfasserin aut Martina Friess verfasserin aut Byron K.Y. Bitanihirwe verfasserin aut Alex Soltermann verfasserin aut Bart Vrugt verfasserin aut Emanuela Felley-Bosco verfasserin aut Raphael Bueno verfasserin aut William G. Richards verfasserin aut Burkhardt Seifert verfasserin aut Rolf Stahel verfasserin aut Walter Weder verfasserin aut Isabelle Opitz verfasserin aut In Molecular Oncology Wiley, 2017 10(2016), 8, Seite 1255-1265 (DE-627)531199800 (DE-600)2322586-5 18780261 nnns volume:10 year:2016 number:8 pages:1255-1265 https://doi.org/10.1016/j.molonc.2016.06.005 kostenfrei https://doaj.org/article/12c600ed6875413da0735385b2c80c20 kostenfrei https://doi.org/10.1016/j.molonc.2016.06.005 kostenfrei https://doaj.org/toc/1574-7891 Journal toc kostenfrei https://doaj.org/toc/1878-0261 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2016 8 1255-1265 |
allfieldsSound |
10.1016/j.molonc.2016.06.005 doi (DE-627)DOAJ095543929 (DE-599)DOAJ12c600ed6875413da0735385b2c80c20 DE-627 ger DE-627 rakwb eng RC254-282 Mayura Meerang verfasserin aut Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma 2016 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Introduction Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methods Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre‐ and post‐CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H‐score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Results Kaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre‐induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post‐CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre‐ and post‐CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3–0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3–1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7–6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27–4.33, p = 0.006]. Conclusions Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment. Merlin Hippo pathway Survivin Malignant pleural mesothelioma Multimodality treatment Neoplasms. Tumors. Oncology. Including cancer and carcinogens Karima Bérard verfasserin aut Martina Friess verfasserin aut Byron K.Y. Bitanihirwe verfasserin aut Alex Soltermann verfasserin aut Bart Vrugt verfasserin aut Emanuela Felley-Bosco verfasserin aut Raphael Bueno verfasserin aut William G. Richards verfasserin aut Burkhardt Seifert verfasserin aut Rolf Stahel verfasserin aut Walter Weder verfasserin aut Isabelle Opitz verfasserin aut In Molecular Oncology Wiley, 2017 10(2016), 8, Seite 1255-1265 (DE-627)531199800 (DE-600)2322586-5 18780261 nnns volume:10 year:2016 number:8 pages:1255-1265 https://doi.org/10.1016/j.molonc.2016.06.005 kostenfrei https://doaj.org/article/12c600ed6875413da0735385b2c80c20 kostenfrei https://doi.org/10.1016/j.molonc.2016.06.005 kostenfrei https://doaj.org/toc/1574-7891 Journal toc kostenfrei https://doaj.org/toc/1878-0261 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2016 8 1255-1265 |
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Mayura Meerang @@aut@@ Karima Bérard @@aut@@ Martina Friess @@aut@@ Byron K.Y. Bitanihirwe @@aut@@ Alex Soltermann @@aut@@ Bart Vrugt @@aut@@ Emanuela Felley-Bosco @@aut@@ Raphael Bueno @@aut@@ William G. Richards @@aut@@ Burkhardt Seifert @@aut@@ Rolf Stahel @@aut@@ Walter Weder @@aut@@ Isabelle Opitz @@aut@@ |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ095543929</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240414122855.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">240413s2016 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1016/j.molonc.2016.06.005</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ095543929</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ12c600ed6875413da0735385b2c80c20</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">RC254-282</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Mayura Meerang</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2016</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Introduction Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methods Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre‐ and post‐CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H‐score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Results Kaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre‐induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post‐CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre‐ and post‐CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3–0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3–1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7–6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27–4.33, p = 0.006]. Conclusions Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Merlin</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Hippo pathway</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Survivin</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Malignant pleural mesothelioma</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Multimodality treatment</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Neoplasms. Tumors. Oncology. 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Mayura Meerang |
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Mayura Meerang misc RC254-282 misc Merlin misc Hippo pathway misc Survivin misc Malignant pleural mesothelioma misc Multimodality treatment misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma |
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RC254-282 Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma Merlin Hippo pathway Survivin Malignant pleural mesothelioma Multimodality treatment |
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misc RC254-282 misc Merlin misc Hippo pathway misc Survivin misc Malignant pleural mesothelioma misc Multimodality treatment misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
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misc RC254-282 misc Merlin misc Hippo pathway misc Survivin misc Malignant pleural mesothelioma misc Multimodality treatment misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
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Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma |
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Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma |
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Mayura Meerang Karima Bérard Martina Friess Byron K.Y. Bitanihirwe Alex Soltermann Bart Vrugt Emanuela Felley-Bosco Raphael Bueno William G. Richards Burkhardt Seifert Rolf Stahel Walter Weder Isabelle Opitz |
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10.1016/j.molonc.2016.06.005 |
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low merlin expression and high survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma |
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RC254-282 |
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Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma |
abstract |
Introduction Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methods Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre‐ and post‐CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H‐score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Results Kaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre‐induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post‐CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre‐ and post‐CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3–0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3–1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7–6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27–4.33, p = 0.006]. Conclusions Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment. |
abstractGer |
Introduction Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methods Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre‐ and post‐CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H‐score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Results Kaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre‐induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post‐CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre‐ and post‐CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3–0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3–1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7–6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27–4.33, p = 0.006]. Conclusions Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment. |
abstract_unstemmed |
Introduction Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methods Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre‐ and post‐CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H‐score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Results Kaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre‐induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post‐CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre‐ and post‐CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3–0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3–1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7–6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27–4.33, p = 0.006]. Conclusions Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment. |
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title_short |
Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma |
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https://doi.org/10.1016/j.molonc.2016.06.005 https://doaj.org/article/12c600ed6875413da0735385b2c80c20 https://doaj.org/toc/1574-7891 https://doaj.org/toc/1878-0261 |
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Karima Bérard Martina Friess Byron K.Y. Bitanihirwe Alex Soltermann Bart Vrugt Emanuela Felley-Bosco Raphael Bueno William G. Richards Burkhardt Seifert Rolf Stahel Walter Weder Isabelle Opitz |
author2Str |
Karima Bérard Martina Friess Byron K.Y. Bitanihirwe Alex Soltermann Bart Vrugt Emanuela Felley-Bosco Raphael Bueno William G. Richards Burkhardt Seifert Rolf Stahel Walter Weder Isabelle Opitz |
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RC - Internal Medicine |
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10.1016/j.molonc.2016.06.005 |
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RC254-282 |
up_date |
2024-07-03T15:11:10.056Z |
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NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein‐1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. Material and methods Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre‐ and post‐CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H‐score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). Results Kaplan–Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre‐induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post‐CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre‐ and post‐CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). 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score |
7.3993187 |