Improved Survival in Osteosarcoma Patients with Atypical Low Vascularization

Pierre Kunz, Joerg Fellenberg, Linda Moskovszky, Z. Sápi, T. Krenács, Isidro Machado, Johannes Poeschl, Burkhard Lehner, M. Szendrői, Peter Ruef, Michael Bohlmann, Antonio Llombart Bosch, Volker Ewerbeck, Ralf Kinscherf, Benedikt Fritzsching

Research output: Contribution to journalArticle

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Abstract

Methods: Computer-assisted whole-slide analysis, together with enzymatic epitope retrieval, was used for CD31-based microvessel quantification in 131 pretreatment formalin-fixed and paraffin-embedded biopsies from three bone tumor centers. Kaplan–Meier-estimated survival and chemoresponse were determined and multivariate analysis was performed. Conventional hot-spot-based microvessel density (MVD) determination was compared with whole-slide imaging.

Background: Osteosarcoma is considered a highly vascularized bone tumor with early metastatic dissemination through intratumoral blood vessels mostly into the lung. Novel targets for therapy such as tumor vascularization are highly warranted since little progress has been achieved in the last 30 years. However, proof of relevance for vascularization as a major prognostic parameter has been hampered by tumor heterogeneity, difficulty in detecting microvessels by immunohistochemistry, and small study cohorts. Most recently, we demonstrated that highly standardized whole-slide imaging could overcome these limitations (Kunz et al., PloS One 9(3):e90727, 2014). In this study, we applied this method to a multicenter cohort of 131 osteosarcoma patients to test osteosarcoma vascularization as a prognostic determinant.

Results: We detected high estimated overall (p ≤ 0.008) and relapse-free (p ≤ 0.004) survival in 25 % of osteosarcoma patients with low osteosarcoma vascularization in contrast to other patient groups. Furthermore, all patients with low osteosarcoma vascularization showed a good response to neoadjuvant chemotherapy. Comparison of conventional MVD determination with whole-slide imaging suggests false high quantification or even exclusion of samples with low osteosarcoma vascularization due to difficult CD31 detection in previous studies.

Conclusion: Low intratumoral vascularization at the time of diagnosis is a strong predictor for prolonged survival and good response to neoadjuvant chemotherapy in osteosarcoma.

Original languageEnglish
Pages (from-to)489-496
Number of pages8
JournalAnnals of Surgical Oncology
Volume22
Issue number2
DOIs
Publication statusPublished - 2014

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Osteosarcoma
Survival
Microvessels
Neoplasms
Bone and Bones
Drug Therapy
Paraffin
Formaldehyde
Blood Vessels
Epitopes
Cohort Studies
Multivariate Analysis
Immunohistochemistry
Biopsy
Recurrence
Lung

ASJC Scopus subject areas

  • Surgery
  • Oncology
  • Medicine(all)

Cite this

Improved Survival in Osteosarcoma Patients with Atypical Low Vascularization. / Kunz, Pierre; Fellenberg, Joerg; Moskovszky, Linda; Sápi, Z.; Krenács, T.; Machado, Isidro; Poeschl, Johannes; Lehner, Burkhard; Szendrői, M.; Ruef, Peter; Bohlmann, Michael; Bosch, Antonio Llombart; Ewerbeck, Volker; Kinscherf, Ralf; Fritzsching, Benedikt.

In: Annals of Surgical Oncology, Vol. 22, No. 2, 2014, p. 489-496.

Research output: Contribution to journalArticle

Kunz, P, Fellenberg, J, Moskovszky, L, Sápi, Z, Krenács, T, Machado, I, Poeschl, J, Lehner, B, Szendrői, M, Ruef, P, Bohlmann, M, Bosch, AL, Ewerbeck, V, Kinscherf, R & Fritzsching, B 2014, 'Improved Survival in Osteosarcoma Patients with Atypical Low Vascularization', Annals of Surgical Oncology, vol. 22, no. 2, pp. 489-496. https://doi.org/10.1245/s10434-014-4001-2
Kunz, Pierre ; Fellenberg, Joerg ; Moskovszky, Linda ; Sápi, Z. ; Krenács, T. ; Machado, Isidro ; Poeschl, Johannes ; Lehner, Burkhard ; Szendrői, M. ; Ruef, Peter ; Bohlmann, Michael ; Bosch, Antonio Llombart ; Ewerbeck, Volker ; Kinscherf, Ralf ; Fritzsching, Benedikt. / Improved Survival in Osteosarcoma Patients with Atypical Low Vascularization. In: Annals of Surgical Oncology. 2014 ; Vol. 22, No. 2. pp. 489-496.
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abstract = "Methods: Computer-assisted whole-slide analysis, together with enzymatic epitope retrieval, was used for CD31-based microvessel quantification in 131 pretreatment formalin-fixed and paraffin-embedded biopsies from three bone tumor centers. Kaplan–Meier-estimated survival and chemoresponse were determined and multivariate analysis was performed. Conventional hot-spot-based microvessel density (MVD) determination was compared with whole-slide imaging.Background: Osteosarcoma is considered a highly vascularized bone tumor with early metastatic dissemination through intratumoral blood vessels mostly into the lung. Novel targets for therapy such as tumor vascularization are highly warranted since little progress has been achieved in the last 30 years. However, proof of relevance for vascularization as a major prognostic parameter has been hampered by tumor heterogeneity, difficulty in detecting microvessels by immunohistochemistry, and small study cohorts. Most recently, we demonstrated that highly standardized whole-slide imaging could overcome these limitations (Kunz et al., PloS One 9(3):e90727, 2014). In this study, we applied this method to a multicenter cohort of 131 osteosarcoma patients to test osteosarcoma vascularization as a prognostic determinant.Results: We detected high estimated overall (p ≤ 0.008) and relapse-free (p ≤ 0.004) survival in 25 {\%} of osteosarcoma patients with low osteosarcoma vascularization in contrast to other patient groups. Furthermore, all patients with low osteosarcoma vascularization showed a good response to neoadjuvant chemotherapy. Comparison of conventional MVD determination with whole-slide imaging suggests false high quantification or even exclusion of samples with low osteosarcoma vascularization due to difficult CD31 detection in previous studies.Conclusion: Low intratumoral vascularization at the time of diagnosis is a strong predictor for prolonged survival and good response to neoadjuvant chemotherapy in osteosarcoma.",
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T1 - Improved Survival in Osteosarcoma Patients with Atypical Low Vascularization

AU - Kunz, Pierre

AU - Fellenberg, Joerg

AU - Moskovszky, Linda

AU - Sápi, Z.

AU - Krenács, T.

AU - Machado, Isidro

AU - Poeschl, Johannes

AU - Lehner, Burkhard

AU - Szendrői, M.

AU - Ruef, Peter

AU - Bohlmann, Michael

AU - Bosch, Antonio Llombart

AU - Ewerbeck, Volker

AU - Kinscherf, Ralf

AU - Fritzsching, Benedikt

PY - 2014

Y1 - 2014

N2 - Methods: Computer-assisted whole-slide analysis, together with enzymatic epitope retrieval, was used for CD31-based microvessel quantification in 131 pretreatment formalin-fixed and paraffin-embedded biopsies from three bone tumor centers. Kaplan–Meier-estimated survival and chemoresponse were determined and multivariate analysis was performed. Conventional hot-spot-based microvessel density (MVD) determination was compared with whole-slide imaging.Background: Osteosarcoma is considered a highly vascularized bone tumor with early metastatic dissemination through intratumoral blood vessels mostly into the lung. Novel targets for therapy such as tumor vascularization are highly warranted since little progress has been achieved in the last 30 years. However, proof of relevance for vascularization as a major prognostic parameter has been hampered by tumor heterogeneity, difficulty in detecting microvessels by immunohistochemistry, and small study cohorts. Most recently, we demonstrated that highly standardized whole-slide imaging could overcome these limitations (Kunz et al., PloS One 9(3):e90727, 2014). In this study, we applied this method to a multicenter cohort of 131 osteosarcoma patients to test osteosarcoma vascularization as a prognostic determinant.Results: We detected high estimated overall (p ≤ 0.008) and relapse-free (p ≤ 0.004) survival in 25 % of osteosarcoma patients with low osteosarcoma vascularization in contrast to other patient groups. Furthermore, all patients with low osteosarcoma vascularization showed a good response to neoadjuvant chemotherapy. Comparison of conventional MVD determination with whole-slide imaging suggests false high quantification or even exclusion of samples with low osteosarcoma vascularization due to difficult CD31 detection in previous studies.Conclusion: Low intratumoral vascularization at the time of diagnosis is a strong predictor for prolonged survival and good response to neoadjuvant chemotherapy in osteosarcoma.

AB - Methods: Computer-assisted whole-slide analysis, together with enzymatic epitope retrieval, was used for CD31-based microvessel quantification in 131 pretreatment formalin-fixed and paraffin-embedded biopsies from three bone tumor centers. Kaplan–Meier-estimated survival and chemoresponse were determined and multivariate analysis was performed. Conventional hot-spot-based microvessel density (MVD) determination was compared with whole-slide imaging.Background: Osteosarcoma is considered a highly vascularized bone tumor with early metastatic dissemination through intratumoral blood vessels mostly into the lung. Novel targets for therapy such as tumor vascularization are highly warranted since little progress has been achieved in the last 30 years. However, proof of relevance for vascularization as a major prognostic parameter has been hampered by tumor heterogeneity, difficulty in detecting microvessels by immunohistochemistry, and small study cohorts. Most recently, we demonstrated that highly standardized whole-slide imaging could overcome these limitations (Kunz et al., PloS One 9(3):e90727, 2014). In this study, we applied this method to a multicenter cohort of 131 osteosarcoma patients to test osteosarcoma vascularization as a prognostic determinant.Results: We detected high estimated overall (p ≤ 0.008) and relapse-free (p ≤ 0.004) survival in 25 % of osteosarcoma patients with low osteosarcoma vascularization in contrast to other patient groups. Furthermore, all patients with low osteosarcoma vascularization showed a good response to neoadjuvant chemotherapy. Comparison of conventional MVD determination with whole-slide imaging suggests false high quantification or even exclusion of samples with low osteosarcoma vascularization due to difficult CD31 detection in previous studies.Conclusion: Low intratumoral vascularization at the time of diagnosis is a strong predictor for prolonged survival and good response to neoadjuvant chemotherapy in osteosarcoma.

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