PI3K/mTOR Signaling in Mesothelioma Patients Treated with Induction Chemotherapy Followed by Extrapleural Pneumonectomy Byron K.Y. Bitanihirwe, PhD,

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PI3K/mTOR Signaling in Mesothelioma Patients Treated with Induction Chemotherapy Followed by Extrapleural Pneumonectomy Byron K.Y. Bitanihirwe, PhD, Mayura Meerang, PhD, Martina Friess, VMD, Alex Soltermann, MD, Lukas Frischknecht, MD, Svenja Thies, MD, Emanuela Felley-Bosco, PhD, Ming-Sound Tsao, MD, Ghassan Allo, MD, Marc de Perrot, MD, Burkhardt Seifert, PhD, Holger Moch, MD, Rolf Stahel, MD, Walter Weder, MD, Isabelle Opitz, MD Journal of Thoracic Oncology Volume 9, Issue 2, Pages 239-247 (February 2014) DOI: 10.1097/JTO.0000000000000055 Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Immunohistochemical staining of PTEN, p-S6, and p-mTOR in MPM in an epithelioid subtype. Hematoxylin and eosin staining of respective MPM cores (A and E). Cytoplasmic and nuclear PTEN expression (B—strong and F—Weak). Cytoplasmic expression of p-S6 (C—strong and G—weak). Cytoplasmic expression of p-mTOR (D—strong and H—weak). Cyto = cytoplasm; Nuc = nucleus; PTEN, phosphatase and tensin homologue; p-mTOR, phospho-mammalian target of rapamycin; MPM, malignant pleural mesothelioma. Journal of Thoracic Oncology 2014 9, 239-247DOI: (10.1097/JTO.0000000000000055) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Box and whisker plots of expression levels of PTEN (cytoplasmic and nuclear), p-S6, p-mTOR, Ki-67, and cleaved caspase-3 in paired MPM data sets from pre- and postchemotherapy (CTX) biopsies. A, Expression levels (H-score) of cytoplasmic PTEN (p = 0.04), nuclear PTEN (p < 0.0005), p-S6 (p < 0.0005), and p-mTOR (p < 0.0005) were significantly reduced after CTX. B, Ki-67 proliferation index was significantly reduced after CTX (p < 0.0005). C, Apoptotic index by means of cleaved caspase-3–positive tumor fractions was significantly increased after CTX (p = 0.03). Significance was calculated with related-samples Wilcoxon signed-rank test. PTEN, phosphatase and tensin homologue; p-mTOR, phospho-mammalian target of rapamycin; MPM, malignant pleural mesothelioma. Journal of Thoracic Oncology 2014 9, 239-247DOI: (10.1097/JTO.0000000000000055) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Kaplan–Meier curves according to PTEN, p-mTOR, p-S6, Ki-67, and cleaved caspase-3 expression levels in malignant pleural mesothelioma tissue samples. A, High p-S6 expression before chemotherapy (CTX) is associated with shorter PFS: patients with low to moderate p-S6 expression (median PFS = 16 months, 95% CI, 12–21, versus high p-S6 = 12 months, 95% CI, 5–18) (cohort 1, n = 75); Kaplan–Meier estimates of median time to progression (log rank test: p = 0.02). B, High Ki-67 proliferation index before chemotherapy is significantly associated with shorter PFS (low to moderate Ki-67 = 18 months, 95% CI, 13–23, against high Ki-67 = 12 months, 95% CI, 10–13) (cohort 1, n = 74); Kaplan–Meier estimates of median time to progression (log rank test: p = 0.04). C, Ki-67 proliferation index after chemotherapy is significantly associated with shorter PFS (low to moderate Ki-67 = 16 months, 95% CI, 10–21, against high Ki-67 = 14 months, 95% CI, 10–17) (cohort 1 n = 101); Kaplan–Meier estimates of median time to progression (log rank test: p = 0.03). D, High Ki-67 proliferation index after chemotherapy is significantly associated with shorter OAS (low to moderate nuclear Ki-67 = 22 months, 95% CI, 17–27 months, against high Ki-67 = 20 months, 95% CI, 15–25 months) (cohort 1 n = 101); Kaplan–Meier estimates of OAS (log rank test: p =0.02). E, Reduced cytoplasmic PTEN expression is significantly associated with shorter OAS (decreased PTEN = 19 months, 95% CI, 13–24 months, against increased PTEN = 23 months, 95% CI, 16–30 months) (cohort 1 n = 75); Kaplan–Meier estimate for OAS (log rank test: p = 0.04). F, Increased cytoplasmic p-mTOR expression is significantly associated with shorter OAS (decreased p-mTOR = 23 months, 95% CI, 18–28, against increased p-mTOR = 11 months, 95% CI, 5–17 months) (cohort 1 n= 66); Kaplan–Meier estimate for OAS (log rank test: p = 0.03). PFS, progression-free survival; OAS, overall survival; PTEN, phosphatase and tensin homologue; CI, confidence interval. Journal of Thoracic Oncology 2014 9, 239-247DOI: (10.1097/JTO.0000000000000055) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions