Induction of senescence markers after neo-adjuvant chemotherapy of malignant pleural mesothelioma and association with clinical outcome: an exploratory analysis

Our plain-English summary of Induction of senescence markers after neo-adjuvant chemotherapy of malignant pleural mesothelioma and association with clinical outcome: an exploratory analysis, by R. Sidi, G. Pasello, I. Opitz, et al (European Journal of Cancer, 2011).

The study

• Authors: R. Sidi, G. Pasello, I. Opitz, A. Soltermann, M. Tutic, H. Rehrauer, W. Weder, R.A. Stahel, E. Felley-Bosco
• Journal: European Journal of Cancer
• Published: 2011;47(2):326-32
• Cited by: 57 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The aim of this study was to assess the induction of senescence markers versus apoptosis pathways in malignant pleural mesothelioma (MPM) tumour samples before and after neo-adjuvant platinum-based chemotherapy and to investigate their relationship with clinical outcome. Specific senescence pathways were assessed by quantifying the expression of p21 and plasminogen activator inhibitor-1 (PAI-1) for the p21-p53 pathway, IGFBP7 for the IGF pathway and ALDH1A3 for the IFN pathway. p21 and PAI-1 expression were also assessed by immunohistochemistry. In addition, beta-galactosidase activity staining at pH 6.0 was performed. Apoptosis was determined by TUNEL assay. Clinical outcome was assessed by modified RECIST criteria, progression-free and overall survival. In a training set (n=9 patients) paired comparison demonstrated a significant increase in p21 (p<0.05), PAI-1 (p<0.01) and apoptosis (p<0.01) after neo-adjuvant chemotherapy. The patients with the highest increase in PAI-1 had stable disease, whilst patients with little change in senescence markers accompanied by a high increase in apoptosis had an objective response after chemotherapy. The hypothesis that stable disease might be associated with an increase in senescence markers was confirmed in a tissue microarray (n=26 patients) using p21 and PAI-1 immunohistochemistry as readouts. For patients where survival and time to progression data were available, increased PAI-1 levels were significantly associated with a worst outcome. Our results demonstrate induction of senescence markers by neo-adjuvant chemotherapy in a proportion of patients with MPM and its potential association with a poor outcome.

Copyright © 2010 Elsevier Ltd. All rights reserved.

In plain English

The authors examined tumour tissue from patients with malignant pleural mesothelioma treated at the University Hospital of Zurich between May 1999 and January 2009. All received chemotherapy planned before surgery: cisplatin with gemcitabine, or cisplatin with pemetrexed. They identified 31 patients (29 males, 2 females) with tumour samples from before and after chemotherapy; 30 later had chest surgery. They measured markers of senescence (cells stop dividing but stay active) and of apoptosis (cell death). In nine patients, the senescence markers p21 and PAI-1 rose significantly after chemotherapy. In six patients, apoptotic cells rose from 1% to 8% of cells. Among 23 patients with response data, those with stable disease tended more often to show a PAI-1 rise than those whose tumours shrank. A rise in PAI-1 was significantly associated with poorer overall survival (p = 0.0098, 21 patients) and shorter time to progression (p = 0.022, 20 patients). The authors concluded that increased PAI-1 was associated with lack of response to chemotherapy. They noted that too few frozen samples were available to settle the link with another senescence test. The study did not examine asbestos exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Exploratory laboratory analysis of paired tumour samples taken before and after neo-adjuvant chemotherapy, compared with clinical outcome (response, survival, time to progression)
• Who was studied: 31 patients with malignant pleural mesothelioma (29 males, 2 females, median age 59, range 44 to 72) treated at the University Hospital of Zurich, Switzerland, between May 1999 and 31 January 2009, with tumour material available before and after chemotherapy. Subsets: 9 patients (training set, RNA), 6 of these for apoptosis testing, 26 patients for tissue microarray (23 with response data). Also 6 normal pleura samples from patients having thoracic surgery unrelated to mesothelioma.
• Exposure: Neo-adjuvant (pre-surgery) platinum-based chemotherapy: three cycles of cisplatin plus gemcitabine (5 patients) or cisplatin plus pemetrexed (26 patients). Asbestos exposure was not studied.
• Main results:
  • 30 patients underwent thoracotomy (explorative in 3, pleurectomy/decortication in 6, extrapleural pneumonectomy in 21). One patient had tumour material taken by lymph node biopsy after chemotherapy and did not undergo thoracotomy.
  • In the training set of 9 patients, expression of the senescence markers p21 (p less than 0.05) and PAI-1 (p less than 0.01) increased significantly after chemotherapy. ALDH1A3 and IGFBP7 did not change.
  • The increase in PAI-1 was statistically significant in patients with stable disease (n = 4) but not in patients with partial response (n = 5)
  • In 6 of the 9 patients, apoptosis was detected in 1% (range 0 to 4) of cells before and 8% (range 1.5 to 15) after chemotherapy, a significant increase (p less than 0.01)
  • Among these six patients, objective radiological responses were seen only in patients with induction of apoptosis and no change in PAI-1
  • In the tissue microarray, response data were available for 23 patients (14 stable disease, 9 partial response). Patients with stable disease tended more often to have an increase in PAI-1 than patients with objective response. No trend was evident for p21.
  • Increased PAI-1 was significantly associated with poorer overall survival (p = 0.0098, n = 21) and shorter time to progression (p = 0.022, n = 20). The main text calls the second measure progression-free survival.
• The authors' conclusion: The authors concluded that both apoptosis and senescence can be observed after chemotherapy in malignant pleural mesothelioma, and that increased expression of the senescence marker PAI-1 was associated with lack of response to chemotherapy
• Limitations the authors state:
  • Too few frozen samples were available to determine a definitive association between increased PAI-1 and senescence-associated beta-galactosidase activity
  • mRNA was not available for all patients at both time points, so protein staining on tissue microarrays was used instead
  • For PAI-1, the relationship between mRNA and immunohistochemistry was significant but less stringent (r2 = 0.33) than for p21

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Chemotherapy, Pleural Mesothelioma, Apoptosis, Immunohistochemistry, Modified RECIST (mRECIST), Overall Survival.

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